Four Things About Allopurinol Hypersensitivity Syndrome Save

Hi, I'm Bob Terkeltaub, 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 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 25%. So this is a really important topic in clinical practice and also, you know, hypervigilance 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 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 we've defined higher-risk groups. The risk goes from double to way higher, like eightfold higher, in these risk groups 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*58:01 in the high-risk patients. Normally HLA-B*58:01 is about 1% in those of white ancestry, but we know that it's way higher — 12 to 20% — 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 100 milligrams a day, and even lower with CKD stage three and worse, the go-slow upward titration regimen is a problem because this prolonged time to achieve target of a serum urate of less than six in real-world clinical practice 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 400 to 500 milligrams of allopurinol a day. And in the real world in primary care, rarely is allopurinol prescribed at more than 300 milligrams a day; the average is 200 milligrams a day or so in real-world primary care. So the real-world success with allopurinol of reaching a serum urate target of less than six is only about 20 to 25% or so, maxing out at 30% 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 the definition of rare disease — the official definition — is something that's below 65 cases per 100,000. And in those with white ancestry, you get about 0.7 cases per 10,000 patient-years. So it's rare in those of white ancestry. Again, the white ancestry patients have only about 1% gene frequency of HLA-B*58:01, but HLA-B*58:01 is way higher, as we mentioned, in the high-risk populations for AHS-SCAR. But this really makes it such that it doesn't meet the criteria of a rare disease in the high-risk populations, because the incidence goes up to about three cases per 1,000 allopurinol initiators, and as high as about five in some populations in East Asia. So this is not really a rare disease 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 oxypurinol engages HLA class one binding pockets — and it's a small molecule, it sneaks into the corner of those binding pockets, especially HLA-B*58:01 but not only HLA-B*58:01 — and this is a direct immune activation. There is oligoclonal drug-specific CD8-positive T-cell expansion. It bypasses the normal antigen-presenting cell requirement, the requirement for cellular processing of that antigen. Remember, oxypurinol is a very small molecule, and it's not limited to a specific T-cell receptor V-beta repertoire. So this is a very unusual form of immune-mediated 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 AHSCAR is that there's an overconfidence in the use of HLA-B*5801 screening as a preventative measure. It's great that people do HLA-B*5801 screening in those that are known to be at high risk. It's not an expensive test that costs no more than a PSA for example.

But a recent paper by Campbell and colleagues in JAMA Dermatology showed that the risk of AHSCAR is only about 2/3 predictable in the United States by HLA-B*5801 testing, and that there's another allele, HLA-A*3402, that has an odds ratio that's pretty close to that of HLA-B*5801 for the incidence of AHSCAR. And that's a very rare allele, HLA-A*3402, except in African-American patients. And so we should not be overconfident about HLA-B*5801 screening being 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 about AHSCAR, which is that there's an interferon signature in AHSCAR, and that a marked treatment response has been described in a pretty robust case series of patients with toxic epidermal necrolysis induced by drugs including allopurinol — an incredible treatment response in this disease with a 25% mortality rate otherwise.

This was published in the journal Nature, a very high impact journal, with beautiful data, using various JAK kinase inhibitors. The work was published by Nordmann — T.M. Nordmann — in Nature in 2024.

So a lot of these patients who get AHSCAR just go directly to the burn unit for their Stevens-Johnson syndrome and toxic epidermal necrolysis, and the practitioners who prescribed the allopurinol get out of the loop pretty easily. So if you have the misfortune of somebody in your practice getting AHSCAR, 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. In previous iterations of case series of other immunomodulating 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 a trial of JAK inhibition in any of your patients that have the misfortune of getting AHSCAR 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.