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Hi, I'm Bob Turkle Taub, University of California San Diego Rheumatology, and, we're going to talk about four things, that are relatively new thoughts about allopurinol hypersensitivity syndrome with severe cutaneous adverse reaction. We'll call it AHS scar, which is the standard definition. And the fear of this is justified and ever present in your clinical practices. I'm certain about that. And we've got a spectrum of of of Stevens Johnson syndrome, toxic epidermal necrolysis with blistering rashes, and drug reaction with eosinophilia and systemic symptoms, DRESS with non blistering rashes that comprise the majority of this syndrome of AHS scar.

And you're all aware that AHS scar is severe, and it actually has a mortality rate of about twenty five percent. So this is a really important topic in clinical practice and also of, you know, hyper vigilance in terms of the overall medical care system and regulatory issues such as at the FDA. And the allopurinol starting dose dependence of the AHS syndrome justifies our start low of allopurinol and go slow upwards titration regimen. That is the standard FDA recommended regimen, and this certainly will limit the incidence of of AHS scar. However, there are defined risk factors, although we can't completely predict who gets this, but we know that there's a much higher incidence with CKD stage three or worse, And then we we've defined higher risk groups, and the risk goes from double to way higher, like eight eightfold higher, in these risk groups that that start with African Americans and then even more high risk with various East and South Asian ancestry patients.

It's not every East and South Asian country. For example, Japan is not one of those countries. And this is related, as you are well aware, to a much higher prevalence of HLA B five eight zero one in the high risk patients. Normally, HLA B five eight zero one is about one percent in those of white ancestry, but we know that it's way higher, twelve to twenty percent, in those at much higher risk for allopurinol hypersensitivity syndrome. So what we already feel the impact of in clinical practice is that when we start allopurinol at no more than a hundred milligrams a day and even lower with CKD stage three and and worse, the go slow upward titration regimen is a problem because there's prolonged time to achieve target of a serum urate of less than six in the real world clinical practice practices that we have, and this is due to the multiple uptitration encounters needed to get people to the average dose of allopurinol where the patient will reach a serum urate target of less than six at our bare minimum, and that takes four to five hundred milligrams of allopurinol a day, And in the real world, in primary care, rarely is allopurinol prescribed at more than three hundred milligrams a day.

The average is two hundred milligrams a day or so in real world primary care. So the real world success of, with allopurinol of reaching a serum urate target of less than six, is only about twenty percent, twenty five percent or so, maxes out at thirty percent in primary care. So the things that are relatively new to think about here with AHS scar are four in number. First, it's been thought that this is really just a rare disease. And and the definition of rare disease, the official definition, is something that's below sixty five cases per 100,000.

And, you know, in those with white ancestry, you got about point seven cases per 1,000 patient a year. So it's rare in those of white ancestry. Again, the white ancestry patients have only about one percent gene frequency of HLA B5A1, but HLA B5A1 is way higher, as we mentioned, in the high risk populations for AHS scar. But, like, this this really, you know, makes it such it it doesn't meet the criteria of a rare disease in the high risk populations because the incidence goes up to three per about three cases per one per one thousand allopurinol initiators and as high as about five in some populations in in East Asia. So this is not really a rare disease in in multiple ethnic and racial groups, and we really need to think about that differently.

And then the immune mechanism of AHS scar is really quite unusual, and we've learned that oxypyranil engages HLA class one binding pockets, and and it's a small molecule that sneaks into the corner of those binding pockets, especially HLA B five zero one, but not only HLA B five eight zero one. And this is a direct immune activation. There's oligoclonal drug specific CD eight positive T cell expansion. It bypasses the the normal antigen presenting cell requirement, the requirement for cellular processing of that antigen. Remember, oxy purinol is a very small molecule, and it's not limited to specific T cell receptor V beta repertoire.

So this is a very unusual form of immune media tissue injury with its own type of cytokine storm and major organ damage and hence the high mortality rate. The third thing that we really need to think about here that's relatively new about AHS scar is that there's an overconfidence in the use of HLA B5-eight zero one screening as a preventative measure. It's great that people do HLA B5-eight zero one screening in those that are known to be at high risk. It's not an expensive test. It costs no more than a PSA, for example, but a recent paper by Campbell and colleagues in JAMA Dermatology showed that the the risk of AHS scar is only about two thirds predictable in The United States by HLA B five eight zero one testing and that there's another allele, HLA A 3,402 that HLA A thirty four zero two that has an odds ratio that's that's pretty close to that of of HLA B five out of one for the incidence of AHS scar.

And that's a very rare allele is HLA A3402, except in African American patients. And so we should not be overconfident about the HLA B5-eight zero one screening being like that great as we may have thought for preventing allopurinol hypersensitivity syndrome. And the last new thing to know is probably the most important thing is about AHS scar is that there's an interferon signature in AHS scar, and that marked treatment response has been described in a pretty robust case series of of patients with toxic epidermal necrolysis induced by drugs, including allopurinol, an incredible treatment response in this disease with a twenty five percent mortality rate otherwise. And this was published in the journal Nature, a very high impact journal and beautiful data published a work using various JAK kinase inhibitors, and the work was published by Nordmann, T. M.

Nordmann, in Nature in 2024. And so a lot of these patients who get AHS scar, they just go directly to the burn unit for their Stevens Johnson syndrome and toxic epidermal necrolysis, and then the practitioners who prescribe the allopurinol get out of the loop pretty easily. So if you have the misfortune of somebody in your practice getting AHS scar, it's good to keep up with the burn unit because really the JAK inhibitor treatment has the promise of being the most effective treatment to date and in previous iterations of trials, a case series of other immune modulating drugs. There's just nothing seen like this particular response to JAK inhibitor treatment. It's very hard to do a clinical trial, as we know, in uncommon diseases, so this is the best knowledge we've got right now.

But clearly, thinking about trial of JAK inhibition in any of your patients that have the misfortune of getting AHS scar is a really reasonable thing to raise higher in your consciousness. So I hope this is informative for all of you in clinical practice and appreciate your attention. Thank you.

Hello. My name is Angelo Gaffo. I am a professor of medicine in the division of immunology and clinical rheumatology at the University of Alabama at Birmingham, and I am also the section chief of rheumatology at the Birmingham BA. I will be talking to you all today about a topic which I which I always have enjoyed a lot, which is gout in this case, specifically gout diagnosis. Just as an introduction, gout is a condition quite prevalent condition now estimated at five percent of United States adults, and its diagnosis is very tied up to understanding the clinical presentation of the condition.

Gout primarily manifests itself itself as gout flares, and it's important to understand that gout flares are usually located in joints and periarticular areas, and I wanna emphasize the latter. The gout flares happening around entices and around bursae are also quite common, probably as common as those located intrinsically in the joints. They have a preferential presentation in the lower extremities, very well known podagra. The pain level associated with gout flurals tend to be very high unless they have the patients come to your practice already medicated. There is usually a rapid escalation in the intensity of the pain from the moment the patient is pain free until the moment the pain peaks.

And the flares are usually associated with joint swelling, warmth, erythema, especially in the small joints. And and knowing this this presentation helps you puts you probably sixty to seventy percent on the way to diagnose the condition. A history of repeated flares like the ones I described is quite helpful. A gout usually also the natural history of the disease implies an initial phase of flares like the ones I I mentioned to you that tend tend to disappear after more or less, five to ten days. And and and this and then enters an intercritical period in which the patient is relatively back to their baseline level of pain, or lack of thereof.

And then, without appropriate treatments, these these flares become longer, become more frequent. These intercritical periods tend to shorten or go away completely, and then the patient can enter a chronic phase of chronic joint pain or swelling and or the presence of of tophi, subcutaneous masses of monosodium urate. Some patients rarely can skip that initial phase of flares and go straight to autophagous phase. In our experience, that is uncommon, but it certainly can happen. So understanding this history, gathering this history during the clinical encounter can again put you very, very well into diagnosis.

Galp clinically, which something that absolutely can happen. So uric acid or serum uric, how do we use it in the diagnosis of gout? Serum uric can be informative for a diagnosis of gout. If you capture a patient during the intercritical phase, like, a large majority of patients that are not on urate lowering therapies will be hyperuricemic. Hyperuricemia is technically defined as six point eight milligrams per deciliter.

Usually, patients with gout will present with a hyperglycemia levels of serum urate at seven, eight, or nine or beyond. An elevated serum urate can support a diagnosis of gout. It's not confirmatory, and a normal or low serum urate makes a gout diagnosis less likely. So it's important to understand also that when a patient is presenting during a flare, serum urate can be lower because the inflammatory milieu of the flare can stimulate the the the kidney tubules to excrete more serum urate. And sometimes serum urate can be one or one and a half points below what would be the real level that you will see during an introcritical phase.

So do I check serum urates to help support the diagnosis of gout? I do. But I but I try to contextualize that number depending on on if the patient is in a flare or is not in a flare. They can be informative. Of course, we in rheumatology love to review synovial fluid, and synovial fluid analysis is is is very important.

It can help us differentiate gout from infection, from calcium paraphosphate deposition disease, obtaining Gram stain culture, cell counts can be all quite informative. Looking in looking on the polarized light, you can see the needle the needle like structures that are monosolidined urate crystals that which are negatively birefringent. Do you always need a a crystal confirmation to diagnose gout? You don't. You can diagnose gout on clinical grounds without crystal confirmation.

Sometimes patients will come to your to your visit intercritical, sometimes without a fluid. And although sometimes you can recover a little amount of fluid to examine in patients with that are not having a flare, usually patients do not receive the the the proposal of having an arthrocentesis very well when they are actually not symptomatic. I always obtain conventional radiographs like plain X rays. And because when I find overhanging edge erosions in plain radiographs, that is a very, very confirmatory test for the presence of gout in the right clinical context. So a good history and sometimes some elevated serum.

Rate. You can see these overhanging edge erosions, usually in the first MPP in the foot or in some common in both areas by flares. And, also, you can sometimes find opacities, which can be consistent with tophi that have had microcalcifications within them. What we have been using more commonly now are a ultrasound and dual any of the CAT scan. On the ultrasound, you can sometimes see the double contour sign, which is a layer of monosodium urate overlaying the cartilage.

A trained ultrasonographers can show that very well. And sometimes you can see the erosions, aggregates, the evidence of topaceous deposits in the area around the joint. This is very supportive of a gout diagnosis, again, in the right clinical context. And finally, dual earnings dual energy CT scan has been extremely helpful for us. It's it's relatively easy to obtain.

It's fast. No IV contrast. Can provide a testament of the facial's bulk, and it's quite convenient and and well accepted by patients in those intercritical phases when they are not having a flare. We can send them to to the CT scanner and obtain a very informative scan for gout relatively fast. Problem is that sometimes it's not approved by insurance very easily, but in certain areas like our VA hospital, it's relatively easy to obtain.

So the messages that I want that I wanna encapsulate for you about gout diagnosis, the clinical presentation, basic laboratories, including serum urate, and basic radiology can establish a diagnosis of gout in an important proportion of cases. And although crystal confirmation is desirable and and and quite helpful if you have it, it's not always necessary. And finally, advanced imaging techniques, including ultrasound and do other energy CT scan, can can support the diagnosis, can be quite helpful, particularly useful during intercritical periods. So I'm very happy for the invitation and the opportunity to talk about gout diagnosis, we'll be with you the next time.

Hi, it's Doctor. Janet Pope. I'm recording for AtRoomNow, and you can certainly follow me as well at JanetBirdau. We're talking a lot this recent past about gout. So I wanna give you some Pope's tips for safe use of allopurinol prescribing in patients with gout.

So number one, if using allopurinol for gout, it is a forever medication for most patients. So be sure there's a good reason to prescribe it. The main indications are TOFI, recurrent gout, greater than two attacks per year, after trying lifestyle modification, medication modification, etcetera. And obviously chronic attacks, smoldering, gout, joint damage on x rays. There's other indications prior to chemo if you're going to have a huge breakdown of cells or for uric acid stones, but I'm really talking about the rheumatology indications.

So number one, the traditional thing is to go low and slow with allopurinol dosing. Now I sometimes like to go higher dose and faster, but I'll tell you why that could be wrong. If you go low and slow, you should reduce hypersensitivity reactions and possibly less initial gout flares. Although I often will give prophylaxis at the same time if my patient looks like they'll need it. So my problem is I know that my patient will take a long time to get to target and every time I increase the dose of allopurinol, I'm going to give them more attacks and that doesn't really help adherence.

However, there are some very reasonable data that hypersensitivity reactions and severe flares are more if you start fast. So start at a hundred milligrams, reduce if they're CKD, keep following uric acid and go high as needed getting uric acid to target. The next thing is I usually wait about four to six weeks to redo the uric acid. So often six weeks and then let the patient know to increase their dose or not. FLAIR prophylaxis might be needed, but at least one study shows that you can start up allopurinol right away even if the patient's in an acute attack.

But of course you would be treating the gout attack at the same time, the gout attack to end. And that's important if your patients have one after another attacks. Okay. What about other safety? So people from Southeast Asia are have a higher risk of problems.

So by Southeast Asia, Han, Chinese, Thai, Korean, amongst others. So they have more severe skin reactions, so hypersensitivity reactions. So should they be tested for allopurinol safety if you're going to use it? Probably yes. Should everyone be tested?

No. So the test that you order is an HLA B fifty eight and you're looking for o one as the type of the HLA B fifty eight. And that should be considered part of allopurinol use. If you can't afford it or can't get access to it, then you work your way up. Another pearl that's important is the SGLT2 drugs.

The inhibitors can increase gout initially because they break down purine metabolism. So they work very much like allopurinol. And when the drugs first came out, I noticed patients were getting gout and I didn't know why. And then eventually their uric acid was good and papers have been written about this. It's well described now.

This is another important tip. Be aware of lupus and CKD patients. Our chronic kidney disease patients with lupus that could be from heart failure, from active or previous lupus nephritis, from interstitial nephritis, etcetera, or other reasons, NSAID use, we have to be aware that if I have a patient with lupus and they have CKD, beware very bad to use azathioprine at full dose with allopurinol unless if you want to be sued and really harm your patient. So what should you do? So I have had patients on azathioprine.

If possible, when they have chronic to face gout, I will stop azathioprine and see if they're going to flare or not. And I will stop before I start allopurinol. If you must use azathioprine, you should go to about a quarter of the dose are on. So seventy five percent reduction of the current dose. And you must do at first frequent complete blood counts with a differential because of the cytopenias.

Why does this happen? Allopurinol blocks the xanthine oxidase, which is how azathioprine is metabolized. A safer option is MMF. So I have read on some papers that MMF has less interaction with allopurinol. So it would be preferred over azathioprine, but even then use it with caution and please follow guidelines, test your patient and please discuss with a lupus patient with CKD who needs allopurinol because CKD is a risk as well, about azathioprine and even about not starting it and being very careful.

So I hope these tips are helpful. Some of them are obvious and some of them might not be as known for some of you. Thank you.