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Steven R. Feldman, MD, PhD: Welcome to Medscape InDiscussion Psoriasis. I'm your host, Dr Steve Feldman. This is the final episode of our second season. We'll be talking about pustular psoriasis, including a hot topic: a chronic orphan condition with a new treatment option, a variant of psoriasis called generalized pustular psoriasis (GPP). How is GPP different from other forms of psoriasis? What population-level data do we have about this rare condition? What do we need to know to manage patients who have this severe form of psoriasis? With me to answer those questions is a leading dermato-epidemiologist whose clinical research focuses on improving the care of patients with chronic inflammatory skin diseases. She's led several multi-site collaborative research projects to better understand rare skin diseases like pustular psoriasis. She's currently an assistant professor of dermatology at Brigham and Women's Hospital and Harvard Medical School. Welcome, Megan Noe.
Megan H. Noe, MD, MPH, MSCE: Thanks so much for having me on the podcast today.
Feldman: Super. Before we launch into GPP, let's briefly discuss the more common form of pustular psoriasis, palmoplantar pustulosis or palmar plantar pustular psoriasis. Is this common?
Noe: Generally speaking, it's not. I still consider palmoplantar pustulosis to be an orphan disease just like GPP.
Feldman: When you see people with plaque-type psoriasis who have a few pustules on their palms and soles, what do you call that?
Noe: That's a great question. I think that's something we're still trying to learn a lot about. When we look at genetic studies, we see that there are key differences between plaque psoriasis, including plaque psoriasis that's localized to the palms and soles, and pustular psoriasis. But in clinical practice, I think we really see disease on a spectrum where we see some patients with just plaques, some patients with pustules, and some patients with a mixture of both. So, I think we're still learning the differences between some of these diseases. That's what can make it a challenge to treat in clinic.
Feldman: Are all these variants of palmoplantar psoriasis to pustulosis orphan conditions?
Noe: We think about palmoplantar pustulosis as an orphan condition. It's rare based on the epidemiology studies when we use strict definitions of just pustules. But like I mentioned in clinic, sometimes it can be hard to differentiate. There's more of a blending of phenotypes in true clinical practice.
Feldman: When you talk about doing the epidemiology and clinically looking for pure pustules, are those prospective studies or are those claims-based studies? What kind of studies are being done to assess this?
Noe: There have been some studies in claims databases. I led a large retrospective study that included 20 institutions across the United States and included 10 years' worth of data. I think for rare diseases like pustular psoriasis, you really need to do it retrospectively to be able to get enough data in a short amount of time.
Feldman: Were you reviewing actual chart notes to look for people who just had pustules on the palms and soles?
Noe: We did, yes.
Feldman: Excellent. I worry that when we look at claims databases, that the diagnoses that are listed are based on justifying the treatment we want to give. And, if there's no approved treatment, we put down other diagnoses.
Noe: I think you're right. I think that happens in clinical practice sometimes when you only use a diagnosis code of palmoplantar pustules, the insurance may reject any of their treatments since there are no FDA-approved treatments. So, I agree completely. I think billing codes for these rare diseases may not be completely accurate.
Feldman: When we have no approved treatments, what do we treat with? Do we treat this differently than we treat typical plaque psoriasis?
Noe: Our study found that people tried everything that we use to treat plaque psoriasis in these patients with palmoplantar pustulosis. We found over 20 different treatments used, which really suggests that we, as dermatologists and as experts, don't exactly know what to do. And I think in my own clinical practice, that's what I found so challenging — there's no one treatment that reliably helps all my patients. It's trial and error and finding the right drug for the right person.
Feldman: My general sense is biologics have revolutionized our management of patients with plaque-type psoriasis. Have they been effective for people with pustular psoriasis as well?
Noe: They're not quite as reliable in pustular psoriasis. I totally agree: I think in plaque psoriasis, we have amazing medications. They work well, they're safe. But in pustular psoriasis, the newer biologics still tend to be hit or miss. For some patients, they can get great results; for other patients, they just don't seem to work.
Feldman: And that's true for pustular psoriasis, in general — we're not just talking about GPP?
Noe: Right, both forms of pustular psoriasis.
Feldman: How is GPP different?
Noe: GPP used to be considered (and some people may still consider it) a form of plaque psoriasis, but I think of it as its own separate disease. We can see it in people with and without a history of psoriasis, but it really presents differently. Patients develop generalized erythema all over. They fall into the category of being erythrodermic many times and then also have these sterile pustules all over their skin. A lot of times, patients are systemically ill, and they can have systemic organ dysfunction. A lot of these patients are seen in the emergency room and cared for on the inpatient side.
Feldman: What will we typically do for these patients since we don't have any standard approach?
Noe: We use a lot of the same treatments that we use for plaque psoriasis. A lot of cyclosporine is used, as that's something that typically works quickly. Like I mentioned, a lot of these patients can be sick and in the hospital. Then we can try some of the biologics, but it may be hit or miss about which biologic will work.
Feldman: When you say a lot of cyclosporine is used, how do we know that?
Noe: We did a retrospective study in patients with palmoplantar pustulosis, and we did a very similar study in adults with GPP. We collected information not only about patient characteristics but also on treatment, and cyclosporine was one of the most used treatments for GPP in our study.
Feldman: Was that the study of nearly 100 patients that you all were able to amass?
Noe: Yes. It took 20 different academic medical centers collecting patient data over 10 years. We were able to get about 100 patients, which really speaks to the rarity of GPP.
Feldman: And about a third of those patients required hospitalization?
Noe: Yeah. We collected information about all comers, starting at their first appointment at an institution and then following them forward as long as we could. On initial presentation, about a third of people were seen on the inpatient side.
Feldman: Yeah, I'm surprised it wasn't higher. And then in that study, about two out of three patients were treated with internal treatments. I found that shocking that a third of the patients had this horrible GPP and didn't get a systemic treatment. How is that possible?
Noe: I think it's possible that because this was a retrospective study, I think we were capturing some people who weren't necessarily in a severe flare and instead presented to their dermatologist with some symptoms of GPP. Maybe they had a history of a more severe flare in the past. One of the things that's tricky about GPP is we know it waxes and wanes, but we don't really understand why and when patients flare. I have patients who will flare frequently — once a year or twice a year — and then there are some patients who will have a flare and then won't flare again for several years even off treatment.
Feldman: Fascinating. You mentioned that it may be a different disease and maybe even different genetics. Can you tell me more about that?
Noe: The genetics of psoriasis are very complicated, and over 100 different genes in plaque psoriasis have been identified. But the main genes we see that are involved in plaque psoriasis are less important in pustular psoriasis, specifically GPP. And while we haven't identified all the genetic mutations that are involved in GPP, we have identified one: a deficiency in the interleukin (IL)-36 receptor. That's not something we see in plaque psoriasis but is very important in a subset of patients with pustular psoriasis.
Feldman: I understand that there's families probably in Japan, maybe more than elsewhere, with genetic defects in the IL-36 receptor antagonist. Is that what we're talking about?
Noe: Yes, that can lead to a form of pustular psoriasis. Patients tend to present younger, and there are even some who present in childhood. That represents some but not all the cases that we see of GPP.
Feldman: Whereas in plaque psoriasis, we're typically thinking about IL-23 and tyrosine kinase 2 (TYK2) that mediates the IL-23 signal and then IL-17.
Feldman: With 150 psoriasis genes on one end and IL-36 on the other, there's probably a spectrum of involvement. So, there may be countless different forms of psoriasis with different propensity to form pustules.
Noe: Exactly. And like I mentioned before, when we think about patients with pustular psoriasis, some but not all have a history of plaque psoriasis. So, those patients might be in the middle of the spectrum, whereas patients with only the pustular form might be on that one end with the IL-36.
Feldman: There is now an approved drug — spesolimab — for the treatment of patients with GPP. How on earth can a drug like that be approved if it took you 20 centers and 10 years to accumulate 100 patients with GPP?
Noe: That's a great question. It was an international study performed all over the world. Because this is a rare disease, the way you design clinical trials include fewer patients than you would if we were studying a drug in plaque psoriasis, where there are lots of patients who may want to participate in the clinical trial.
Feldman: I understand they had more study sites than they ended up having study subjects.
Noe: They did, and I know they enrolled a lot of study sites that never enrolled a patient. But they were ready and had the medication so they could if the right patient presented.
Feldman: It was something like 50 subjects overall. Two out of three got the active drug at first, and one out of three got the placebo. One of the things that struck me about the idea of doing a GPP study is that there'd be no way to have a placebo group, because you're dealing with people with this horrible condition that you wouldn't be able to put them on a placebo. How did they manage that?
Noe: One of the key elements of this trial is the study period was only a week. Their drug was so effective that they were able to measure outcomes at 7 days. That's very different than a lot of our other dermatology drugs and specifically in psoriasis, where we see an outcome at 12 weeks or an outcome at 16 weeks.
Feldman: Another thing about GPP is that back in the old days when I used to see it more regularly before we had all these great drugs controlling the plaque psoriasis, we'd have more GPP flare ups. Back then, you'd admit people to the hospital, put them on some topical therapy, and give them IV antibiotics to control whatever infection might have set them off. If you had cyclosporine, maybe give that, or once we had biologics, offer one of the faster-acting biologics like infliximab. But these people would get better in the hospital in just a few days anyway. If you ever did try to do a GPP study, the placebo group might clear up, too. What did they find in the first week of treatment?
Noe: In this study, they were looking at clearance of pustules at about a week. They found that more than half of patients who got spesolimab had clearance of their pustules, and only about 6% of patients on placebo did. So, there was some placebo response but not very much.
Feldman: I understand that most of the patients just got one dose of drug. They could get a second dose, and the placebo group switched over. They go on drug after about 1 week or on day 8 or something like that?
Noe: Yeah, exactly.
Feldman: When I see these study results, I always wonder, what's the true success rate? One of the things that I consider is the percentage of patients who stay in the study. What percentage of the patients need rescue treatment? And it seemed like many more than 50% of the patients did well on the therapy if you use those kinds of things as a measure for failure.
Noe: I agree. I think spesolimab seems like a great drug for people with GPP.
Feldman: Anything else we should know about managing patients with pustular psoriasis?
Noe: I think what we know now is this new drug, spesolimab, is highly effective for treating flares. We just talked about how efficacious it is in the 1-to-2-week period, but I think it's going to be interesting to learn the best way to manage these patients long term. I think of GPP as a chronic disease, so there are ongoing studies now to understand how we should use spesolimab in the long term. Should we wait until people flare? Should we dose it every 4 weeks? Should we dose it every 12 weeks? We don't know yet. But all these studies are ongoing. I think it will be interesting to learn how often and how frequently we need to treat these patients. Some of our newer biologics for plaque psoriasis are only given four times a year, and they keep people clear, which is amazing. So, it will be interesting to see long term the best way to treat these patients with GPP.
Feldman: I think you may have mentioned early on that these people are sick. They may present in the emergency room. Is there anything we should be thinking about improving the diagnosis and how quickly patients can get started on a treatment like this?
Noe: Typically, in the emergency room, the most common concern is infection. Do these patients have a concurrent infection? Like I mentioned, they may present with systemic symptoms, including fevers. So, that needs to be ruled out. I think [it's important to] make emergency department providers aware of the disease, which can be hard because it is so rare. Dermatologists don't see it very frequently, so emergency providers probably don't either. Having dermatologists around and able to evaluate patients in the emergency room is key. I think a dermatologist is important in making diagnosis of not only GPP but also any of these rare skin diseases that present either to the emergency room or on the inpatient side.
Feldman: I think we should point out that spesolimab is an antibody against the IL-36 receptor. So, for those patients who are missing the IL-36 receptor antagonists, it's replacing the underlying thing they're missing. But I imagine IL-36 being part of that IL-31 family might be important for fighting off infection, especially if it's calling in neutrophils. It seems like it would be one of the more basic things you would need for infection fighting. I think in the clinical trial, there was only one serious infection, and if I'm not mistaken, it was a urinary tract infection. The way I look at things when I see GPP, one of the first things I wonder is, does this person have a urinary tract infection causing them to have GPP?
Noe: I think that's a great point. When we looked at our big retrospective study, we did think of infection. In many patients, we identified infection as a trigger for their pustular psoriasis. There was also a concern in the study or a signal for a hypersensitivity reaction. There were only about 50 patients in the trial, so a very small number. So, there is a warning on the package insert for a hypersensitivity or drug reaction with eosinophilia and systemic symptoms (DRESS)-like presentation. When they investigated these cases, they weren't exactly what dermatologists would think of as DRESS that didn't meet our diagnosis criteria. But as we treat more patients in the real world, it will be important to follow and see if additional patients develop this hypersensitivity-type reaction in addition to their GPP.
Feldman: How do you not diagnose DRESS in somebody with GPP who is red all over, and they've got systemic symptoms because they've got GPP? It seems to me that it would be easy to misdiagnose these patients as having DRESS when they don't really have it.
Noe: Exactly. There is lots of overlap in the phenotype and the rash in the way people present.
Feldman: Excellent. Is there anything else we should know about managing patients with pustular psoriasis?
Noe: I think it's important to keep in mind that the old medications still work well. They don't work quickly, but for certain patients, medication like acitretin or cyclosporine can be reliable. And then, understanding which biologics work for which patients. IL-17 inhibitors can be a little bit more effective than some of the other medications. And finally, I'm excited to use more spesolimab and see how that can be a benefit to my patients in the future.
Feldman: Yeah, hopefully you'll have that opportunity being at a major academic center, you might see one. What's one thing you want listeners to do differently after hearing this podcast?
Noe: I think the main thing is to identify patients with GPP. Even as a dermatologist, we don't see these things very often. Keep it in mind. Keep it in your differential for patients who present with erythrodermic symptoms or big, red rash all over and pustules. We want to think about infection and drug but also think about GPP, because now we have a specific treatment just for these patients that can be highly effective. We want to start it as quickly as possible.
Feldman: Super. And if you have patients who have pustular psoriasis, and they want to learn more about it, one of the things you can do is direct patients to the National Psoriasis Foundation website for information. I'll summarize what we've learned today. First, GPP has an enormous impact on patients' lives. Having severe pustular psoriasis is much worse than having plaque psoriasis; it's more like having hidradenitis suppurativa. The second fascinating thing about it is we have some understanding of the basic mechanism: IL-36 signals an inflammatory response, in particular neutrophils. Genetic defects in this IL-36 control pathway, such as not having the receptor antagonist, and can lead to GPP. Other things trigger the mechanism, too, but having an IL-36 receptor antagonist defect puts patients more on the spectrum of pustular disease than typical plaque psoriasis. Given the rarity of pustular psoriasis, it is amazing that researchers managed to design a well-controlled clinical trial showing that spesolimab, an IL-36 receptor blocker, provided relatively rapid control over the disease. Megan, thank you so much for sharing your wisdom with us today.
Noe: Thanks so much for having me on the podcast. This was fun.
Feldman: Thanks for joining our season finale discussion with guest Dr Megan Noe. Be sure to check out the Medscape mobile app and share, save, and subscribe if you enjoyed this episode. If you haven't heard our earlier discussions about psoriasis management, you can find the previous episodes on the Medscape app. Thanks again for listening. I'm Dr Steve Feldman for Medscape InDiscussion.
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Cite this: Red Rash and Pustules All Over? Here's What to Know - Medscape - Aug 24, 2023.