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CPD

Challenges and Opportunities in the Management of Generalized Pustular Psoriasis

  • Authors: Melinda Gooderham, MD
  • CPD Released: 12/4/2020
  • THIS ACTIVITY HAS EXPIRED FOR CREDIT
  • Valid for credit through: 12/4/2021, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for an international audience of non-US dermatologists and primary care physicians involved in the management of patients with generalized pustular psoriasis (GPP).

The goal of this activity is to describe clinical presentation of GPP and the impact on patients' lives, and as well as to provide top experts' tips on practical aspects of GPP management to optimize patient outcomes.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Etiopathogenesis of GPP
    • Impact of GPP on patients' lives
  • Have greater confidence related to
    • Managing patients with GPP to optimize patient outcomes


Disclosures

WebMD Global requires each individual who is in a position to control the content of one of its educational activities to disclose any relevant financial relationships occurring within the past 12 months that could create a conflict of interest.


Faculty

  • Melinda Gooderham, MD

    Assistant Professor
    Queens University 
    Kingston, Ontario, Canada
    Probity Medical Research 
    Waterloo, Ontario, Canada
    Medical Director
    SKiN Centre for Dermatology 
    Investigator
    Consultant Physician
    Peterborough Regional Health Centre 
    Peterborough, Ontario, Canada 

    Disclosures

    Disclosure: Melinda Gooderham, MD, has disclosed the following relevant financial relationships:  
    Served as an advisor or consultant for: AbbVie Inc.; Amgen Inc.; Arcutis; Bristol Myers Squibb Company; Boehringer Ingelheim Pharmaceuticals, Inc.; Eli Lilly and Company; Janssen Pharmaceuticals; Kyowa Kirin; LEO; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; Sun Pharmaceutical Industries, Ltd.  
    Served as a speaker or a member of a speakers bureau for: AbbVie Inc.; Amgen Inc.; Boehringer Ingelheim Pharmaceuticals, Inc.; Celgene Corporation; Eli Lilly and Company; Galderma Laboratories, L.P.; Genzyme Corporation; Janssen Pharmaceuticals; LEO Pharma; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Regeneron Pharmaceuticals, Inc.; Sanofi; UCB Pharma, Inc.; Valeant Pharmaceuticals International  
    Received grants for clinical research from: AbbVie Inc.; Akros;  Amgen Inc.; Arcutis; Bristol Myers Squibb Company; Boehringer Ingelheim Pharmaceuticals, Inc.; Celgene Corporation; Dermavant; Eli Lilly and Company; Galderma Laboratories, L.P.; Incyte Corporation; Janssen Pharmaceuticals; Kyowa Kirin; LEO Pharma; MedImmune Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Regeneron Pharmaceuticals, Inc.; Sanofi Genzyme Corporation; Sun Pharmaceutical Industries, Ltd.; Valeant Pharmaceuticals International   

Editors

  • Briana Betz, PhD

    Medical Education Director, WebMD Global, LLC

    Disclosures

    Disclosure: Briana Betz, PhD, has disclosed no relevant financial relationships.

  • Heather Lewin, MAT

    Director, WebMD Global, LLC

    Disclosures

    Disclosure: Heather Lewin, MAT, has disclosed no relevant financial relationships.

Content Reviewer

  • Robert Morris, PharmD

    Associate Director, Accreditation and Compliance

    Disclosures

    Disclosure: Robert Morris, PharmD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: ViiV Healthcare
    Owns stock, stock options, or bonds from: GlaxoSmithKline

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.


Accreditation Statements

    For Physicians

  • The Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the United Kingdom (FPM) has reviewed and approved the content of this educational activity and allocated it 0.50 continuing professional development credits (CPD).

    Contact WebMD Global

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]


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CPD

Challenges and Opportunities in the Management of Generalized Pustular Psoriasis

Authors: Melinda Gooderham, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED FOR CREDIT

CPD Released: 12/4/2020

Valid for credit through: 12/4/2021, 11:59 PM EST

processing....

 

Melinda Gooderh...: Hello, I'm Melinda Gooderham, a dermatologist and clinical researcher from the SKiN Centre for Dermatology in Queens University in Peterborough, Ontario. Welcome to this program entitled The Challenges and Opportunities in the Management of Generalized Pustular Psoriasis. In this program, I will summarize key clinical information presented by me and my colleagues, Professor Ulrich Mrowietz and Dr. Abby Van Voorhees [00:00:30] at a virtual live symposium. If you would like additional resources, please see the accompanying audio and slides from the full symposium.

Recently, there has been a European consensus statement on the definition of generalized pustular psoriasis or GPP. They define this as a primary eruption of sterile macroscopically visible pustules on non-acral skin. So not including those cases where pustulation [00:01:00] develops within the psoriatic plaque, this is on the rest of the skin. Then there are various subclassifiers that have been identified. So patients can present with or without systemic inflammation, with or without concomitant psoriasis vulgaris or a history of psoriasis vulgaris, and the subclassifier of either a relapsing condition where they've had it for more than one episode, or where it's persistent and has been present for greater than three months.

[00:01:30] So here would be a typical presentation of a patient with generalized pustular psoriasis and you can see that widespread erythema that is studded with specific pustules, which can then coalesce to form lakes of pus. When these dry out, you can see that there's desquamation of the skin leaving superficial erosions widespread, and you can also see that background of erythema, which can sometimes develop into an erythrodermic picture.

[00:02:00] So in the European Consensus Statement, they looked at what are the clinical features of GPP that have been defined in our most popular dermatology textbooks. They compared a number of these textbook definitions of pustular psoriasis and saw some similarities and some differences. For example, they can present with concomitant fever, generalized pustules, which are sterile, localized to the trunk and extremities, maybe localized in intertriginous areas, and then there are some definitions [00:02:30] that included arthritis. But you can see here that there's not complete agreement on the clinical features in each of these definitions from the textbooks. So I think there really needs to be better agreement on the clinical features, which was one purpose of this European consensus.

So we do know that GPP can develop in people with preexisting psoriasis, or it can develop de novo. There's a degree of overlap with other pustular diseases, and when [00:03:00] patients initially present, they can present with fever, chills, or just a generalized feeling of being unwell. They may present with a more generalized eruption to start, or it may start in certain areas and spread, like spreading to the trunk and extremities from the intertriginous areas. There can be different patterns that present. Some present very sick with sepsis-like symptoms. So they can be very seriously [00:03:30] ill, requiring admission to hospital for hemodynamic stabilization or further investigations.

The subsequent events after the initial presentation within hours, they can present with the eruption, these densely seeded pustules, as you saw in the photograph, anywhere from one millimeter to three millimeters in diameter. And then these can become confluent forming these lakes of pus. And as I mentioned, these are typically on the trunk and extremities.

[00:04:00] There's been a lot of further investigation into characterizing GPP and who is more at risk looking at getting GPP compared to other forms of pustular psoriasis. So we actually have a family of pustular psoriasis conditions, including the generalized form or generalized pustular psoriasis GPP, but we also have the localized forms, palmoplantar pustulosis and acrodermatitis continua of Hallopeau. In this [00:04:30] genetic study that they looked at, they had a cohort of over 800 people with forms of pustular psoriasis and of those 800 plus patients, they had genetic samples from 475. So they were able to do a lot of analysis on these cases, and it has been the largest cohort to date.

What they found was that the age of presentation was much younger for GPP compared to acrodermatitis of Hallopeau and palmoplantar [00:05:00] pustulosis. They also found that patients with GPP were more likely to have a history of psoriasis vulgaris compared to acrodermatitis and palmoplantar pustulosis. Other features that they saw was the presence of the IL36RN alleles, which is the gene encoding for the interleukin-36 receptor antagonist. They found these alleles across a number of ethnicities, and they also found that [00:05:30] the age of onset was related to the number of interleukin-36RN alleles. So we're definitely learning more information about this group of conditions and sort of the genetic predisposition, but definitely more work needs to be done.

When patients present there's a specific laboratory profile that can be seen in these patients. They usually present with leukocytosis, including neutrophilia, hypocalcemia, hypoalbuminemia, and they [00:06:00] have an elevated sedimentation rate and a high CRP. These have been sort of defined in consensus statements, so this is from the Japanese guidelines where they looked at different severity. So the severity criteria looking at fever, white blood cell count and CRP, and dividing them up into these three specific severity levels. It's interesting based on this analysis of 40 cases of adult GPP, that actually one third [00:06:30] of the population did not have fever. Another third did not have elevated white blood cell count, and a small proportion did not have an elevated CRP. So we can see that there's definitely a range in the severity when patients present with this condition.

We also see a number of comorbidities in patients with GPP. This was based on a retrospective cohort study for Malaysia with over 100 patients. Two thirds of the cohort had at least one comorbidity [00:07:00] and the four most common co-morbidities were hypertension, hyperlipidemia, and diabetes in a quarter of the patients, and obesity in 43% of the patients in this cohort. We do see some reports of other co-morbidities that have been associated, such as thyroid dysfunction, arthritis, ischemic heart disease, and we do see liver abnormalities in about 50% of patients. [00:07:30] This is more associated with male gender, and also lymphocytosis can be correlated with increased bilirubin. The liver enzyme pattern tends to be more cholestatic than cytolytic. This definitely needs to be differentiated from the effects of acitretin therapy, which is a common treatment for these patients. So sometimes it can be hard to differentiate the lab findings based on the current therapies that they're on, or if it's simply related to the underlying condition.

[00:08:00] So one of the other important groups to consider are patients who develop GPP associated with their pregnancy. We do see onset usually in the third trimester, however, the first or second trimester presentation is possible. It can also present in the postpartum period. In these patients, the eruption usually begins in the intertriginous areas and then spreads to the torso and extremities. It can be associated [00:08:30] with poor pregnancy outcomes, including neonatal death. So this needs to be addressed. If patients present in the third trimester, one of the potential treatments could be delivery of the infant to treat the condition. However, if it happens in the first and second trimester where this is not possible, we need to think about what treatments are safe in this patient population.

So the guideline definition for GPP that was defined [00:09:00] in the Japanese guidelines, based on four parameters, a definitive diagnosis can be made if all four parameters are present or a suspected diagnosis with two or three parameters. So the parameters are one, systemic symptoms such as fever and fatigue. Two, systemic or extensive flushing accompanied by multiple sterile pustules that as I mentioned, will merge and form lakes of pus and then lead desquamation. Number three, neutrophils leading to subcorneal [00:09:30] pustules, which would be seen pathologically. Then you would get repeated recurrence of these clinical findings to define this as GPP. So you'll have repeated episodes or a prolonged initial episode.

The clinical course of these patients, as I mentioned, inpatient treatment is usually required because of the instability of the patient. There are some mortality risks associated with this condition and basically close [00:10:00] monitoring and treatment is typically done in an inpatient setting. The course is usually chronic, so it can be ongoing or a remitting and relapsing condition requiring ongoing therapy. It can also be lethal due to infections or circulatory failure. So very important that these patients are closely monitored and require admission to hospital.

Next, I wanted to summarize the understanding that we now have a more clear understanding of the pathogenesis of GPP. [00:10:30] Classically we've defined GPP is a variant of psoriasis. However, it's likely its own distinct clinical entity. And so there's certain reasons why we feel both ways. So the reasons we feel that it's more similar to psoriasis is that patients with psoriasis can develop GPP. We know from gene expression analysis that they have a similar transcriptome between psoriasis and GPP, and that the pathways are closely linked with similar players. So [00:11:00] interleukin-17, -22 TNF and interleukin-36 play a role in both GPP and psoriasis. However, this is in different proportions. So there are differences from psoriasis where we believe it's its own clinical entity. GPP is inclined more towards an innate or non-specific inflammatory response compared to psoriasis, which is basically an adaptive immune response.

Also, interleukin-36 plays [00:11:30] a more prominent role in GPP compared to plaque psoriasis. Whereas interleukin-17 and TNF are more prominent in the plaque psoriasis patients. So we know there are triggering factors in GPP. So we have patients who present with genetic alterations. So these are genetically predisposed. And then you can have triggers such as infection, most commonly and upper respiratory tract infection, [00:12:00] or perhaps a certain medication. Most commonly the withdrawal of systemic steroids can lead to a flare of GPP. And then there are other triggers such as stress or pregnancy, which I just mentioned.

So we know there's a complex pathogenesis and the genetic alterations that have been identified so far, I've already mentioned one, interleukin-36RN, which is the gene that encodes for the interleukin-36 receptor antagonist. But there are other gene alterations [00:12:30] that have been identified as well, including CARD14, which is important for the NF-kappa B pathway, where we have a gain of function. And also the AP1S3 is another gene alteration that has been identified. So what's important is that all of these genes encode for proteins that play an important role in the regulation of inflammation. So when you have an alteration, this leads to a dysregulation of these inflammatory pathways. But to [00:13:00] date only a third of GPP cases are actually explained by this genetic predisposition. So there's still work to be done to get a better understanding. One of the challenges is the rarity of these conditions, and so getting enough patients to learn about the full genetic profile has been a challenge. One clear thing is that there is an important role of interleukin-36 in the pathogenesis of GPP.

So I just wanted to sort of reacquaint you with interleukin- [00:13:30] 36 and give a bit of a review. Interleukin-36 is three cytokines, which belongs to the interleukin-1 superfamily. And this family plays a central role in the regulation of our immune system. So interleukin-36 alpha, beta and gamma, these are the three interleukins that are produced and they're actually produced in their inactive form. And this is one way that we can regulate this type of inflammation. So after they're produced, they're produced in [00:14:00] the inactive form and then they require N-terminal cleavage to become biologically active.

We also have inhibitors of interleukin-36, which is another way that we can control immunity or immune regulation. So the interleukin-36 receptor antagonist is one way and also interleukin-38 is another antagonist of interleukin-36. The interleukin-36 receptor antagonist binds [00:14:30] to the interleukin-36 receptor, and it binds with a higher affinity and a slower off rate than the three interleukin cytokines. So when there's a receptor antagonist present, it does a very good job at preventing unnecessary inflammation from interleukin-36, until there's a situation where we would need that.

So just sort of a quick summary of interleukin-36 function. When we do want to amount an immune response, interleukin-36, which is produced by keratinocytes [00:15:00] will then bind to the interleukin-36 receptor to stimulate this immune response and promote the activation and recruitment of immune cells. So we would do this normally when we want to amount an immune response, however, it can also happen in certain disease states as well. So the role of the receptor antagonist is to control this inflammation and this is how the receptor antagonist works. [00:15:30] It, as I mentioned, binds with high affinity and a slower off rate to the interleukin-36 receptor to block the immune response. And that would be in the normal condition when we're not looking to amount an immune response.

There are some certain situations, however, where you can have an altered receptor antagonists such as in those genetic alterations in the interleukin-36RN gene that I mentioned, and that leads to an altered antagonist, which is not able to bind to the receptor. [00:16:00] So in that situation, you get an unrestrained inflammatory response with production of multiple chemokines and the influx of numerous inflammatory cells.

So let's look at the pathway from start to finish. These keratinocytes will then produce these inactive full length, interleukin-36 cytokines, alpha beta and gamma, and then there's protease activity, which is required to activate that interleukin-36 through the cleavage at the N-terminal. [00:16:30] So the proteases come from neutrophils, cathepsin G, elastase, proteinase 3, and these need to be present for activation. One other way we control this inflammation is that we also have protease inhibitors. So we have all these sorts of checks and balances along the pathway to control our inflammatory responses. So in this situation where the proteases cleave these inactive interleukin-36 are pro interleukin-36 cytokines, [00:17:00] we then get the activated form, which binds to the receptor. Depending on the cell type, if it's a keratinocyte, there may be further production of interleukin-36. So you get an expansion of the response, or it could bind to other immune cells. So for example, the naive T-cell has an interleukin-36 receptor, and so interleukin-36 can help promote the development of the T-cell response.

So if we look at this in the setting of [00:17:30] GPP, we have that pathway going on in the skin where interleukin-36 results in the recruitment of immune cells, be that the number of chemokines, interleukin-8. So we get the attraction of neutrophils into the skin and when the neutrophils collect, they form these pustules, and then you'll get the histologic and the clinical features that we've discussed. You can also get the systemic effects that we've discussed with fever and hemodynamic changes, for example.

Another [00:18:00] thing which is imperative to learn about is the burden on the patients with this condition. There's a clinical burden, which we just discussed, but there's also a humanistic burden and an economic burden of GPP. Although we know there is a burden on the patient, because GPP is so poorly classified, studies are really limited at this point, and we do need a better recognition of this condition and more treatment options to deal with that burden.

[00:18:30] This was a study looking at the impact on quality of life, of various types of psoriasis in a cohort of almost 400 patients comparing different types of psoriasis. And you can see that pustular psoriasis had a very significant impact on quality of life based on the SF-36, more of an impact than plaque psoriasis or guttate psoriasis. And it had a significant impact along the same lines of psoriatic arthritis and palmoplantar psoriasis. So we definitely know [00:19:00] based here on the SF-36 scores, there is a significant impact on quality of life, but more data is definitely needed to show this.

So moving on to the treatments for GPP, we know that there's no approved drug for GPP worldwide. Virtually everything that we use for plaque psoriasis are drugs that have been tried in GPP. And that is based on the similarities with psoriasis that I described [00:19:30] earlier, having similar pathways, although the cytokines have a slightly different importance in their role in the pathogenesis. This identifies high unmet medical needs in the management of this condition. We know that there's a high burden on patients. There's an impact on quality of life. Yet we have no specific treatment to treat it. And we're just using basically what else is in our toolbox.

So the Japanese guidelines [00:20:00] for GPP list the number of different treatments. So the retinoids acitretin and etretinate in Japan, cyclosporine is commonly used, methotrexate, or we move into combinations such as acitretin and methotrexate, cyclosporine and methotrexate. And we've also moved into the biologic therapies for psoriasis where TNF inhibitors have been used as well as many other biologics, including interleukin-17 [00:20:30] inhibitors and interleukin-23 inhibitors. Also in Japan, they've been using a treatment called granulocyte/monocyte apheresis. So basically this is a mechanical removal of these cells from the circulation and therefore a non-pharmacologic therapy.

Here's a publication from Europe, looking at conventional treatment agents that are used in GPP. And this is either used as monotherapy or in combination with biologic therapies. It looks like retinoids and [00:21:00] cyclosporine are the most commonly used agents followed by methotrexate. Steroids are typically reserved for more severe cases or as a rescue therapy. And ultraviolet therapy plays a much smaller role in the management of these patients.

And moving on to biologic agents, infliximab, adalimumab, and etanercept have been used reported here in this French survey on 11 patients with GPP. [00:21:30] Infliximab was used the most and had the highest response rate. Actually, in the live virtual symposium, we did discuss this and it was agreed that from a TNF perspective, infliximab is probably the most effective agent for this condition because it's delivered intravenously and we want something that's going to work fast.

There have also been publications looking at interleukin-17 inhibitors for GPP. This is one publication where they actually looked at GPP and erythrodermic psoriasis, [00:22:00] but this was the GPP cohort shown here. They had 12 patients that were treated with 140 milligrams of brodalumab. And a few of those patients needed a dose increase to 210 milligrams. And here are the results with one limitation is that these analysis is that they use the PASI score, which of course was developed for plaque psoriasis and not GPP. So keeping in mind, the scoring system may not be the most ideal to be used in this [00:22:30] situation. However, if you look at the PASI 100, which is complete resolution of symptoms, you do see that over the 52 weeks, patients did have complete resolution of symptoms and up to 60% of subjects by week 52.

There was another more specific assessment looking at the pustular symptom score over time. And you do see that reduction in the pustular symptom score throughout the 52 week period. There are very wide error bars here [00:23:00] due to the small number of patients and the variability of response to this agent.

Another interleukin-17 inhibitor, ixekizumab was reported here from a single center study. 10 GPP patients from Japan, they used ixekizumab dosing as per the label with what we would use for plaque psoriasis. And, again, we have the limitation here of using the PASI score, but you do see a rapid improvement in symptoms over the first four weeks, which is maintained from week [00:23:30] four throughout to week 24. And then moving on to the interleukin-23 inhibitor guselkumab, that was looked at for GPP as well. You can see the dosing is a bit lower than what we would typically use in psoriasis. Here, they've used 50 milligrams at week zero and four, and then every eight weeks for the 52 weeks the dose increased to 100 milligrams, was allowed from week 20 onward.

[00:24:00] This again was a smaller study in 10 patients, and there's some improvement over the first eight weeks, a couple more resistant patients. You can see the hashed line of those patients, which required a dose escalation. But if you look at the average response, which is the bolded line in the center of the graph, you do see an improvement in the JDA or Japanese Dermatology Association severity index over the 52 week period.

Finally, for [00:24:30] treatments, there has been investigation with an interleukin-36 receptor antagonist, or spesolimab. This was a phase one proof of concept trial. So just one infusion of 10 milligrams per kilogram was given to the patients at baseline. And you can see a rapid improvement in symptoms with the majority of patients over the first week, and then continuing to improve through week four, and then maintaining the change in the GP PASI [00:25:00] from baseline, which is a more specific score for generalized pustular psoriasis, as opposed to the regular PASI. And you can see that maintenance of response throughout the 20 week period based on that one infusion.

So now there was one patient, patient number four, who was a little more resistant to the therapy, but did improve over time. Here are some pictures from that study. You can see patient four here, actually, who had very severe disease at baseline with improvement and [00:25:30] looking great with a GP PGA score of one at week four. So there is significant improvement, and this is just based on one dose. The treatment was also very well tolerated with low rates of adverse events.

So that sort of opens up for future therapies in the treatment of GPP, looking at these interleukin-36 receptor antagonists. There are two in the pipelines, spesolimab, [00:26:00] which I just showed you and another one called imsidolimab. So these are going to be investigated specifically for the purpose of GPP. So it could be that these are the first treatments approved specifically for GPP, but time will tell us further, as studies are done, we need phase two, we need phase three programs first to be completed.

So in conclusion, GPP is a rare disease in the white population. However, it is more common in Asians. [00:26:30] So we see a lot of data and publications coming from the Asia-Pacific region, where we can really learn a lot about this condition. It has led to an increased understanding of the pathogenesis of GPP overall, and sort of the pathogenesis can then help us identify different targets for treatment in the future. So currently there's no approved therapies worldwide. However, we do have new therapies on the horizon. But most importantly, we need to come to a consensus [00:27:00] about the treatment algorithms. We have to be on the same page about the definition of this condition to start with, and then we need to have consensus on the treatment as well, moving forward.

So thank you very much for participating in this activity. Please continue on to answer the questions that follow and then complete the evaluation. Thank you.

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