Dermatology Expert Perspective Series: Generalized Pustular Psoriasis

The current treatment landscape for generalized pustular psoriasis was discussed within a Dermatology Expert Perspective Series hosted by DermatologyTimes^®. Experts interviewed were Raj Chovatiya, MD, PhD, an assistant professor of Dermatology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois; David L. Kaplan, MD, a professor of Dermatology at University of Missouri-Kansas City School of Medicine in Kansas City, Kansas; and Michael Payette, MD, MBA, FAAD, associate professor of Dermatology at University of Connecticut Health Center in Farmington and dermatologist and partner at Central Connecticut Dermatology in Cromwell. This article highlights key points from their interviews.

Raj Chovatiya, MD, PhD, FAAD
Medical Director, Clinical Trials Unit
Assistant Professor of Dermatology
Director, Center for Eczema and Itch
Northwestern Universty Feinberg School of Medicine
Chicago, IL

David L. Kaplan, MD, MS, FAAD, FACP
Professor of Dermatology
University of Missouri-Kansas City School of Medicine
University of Kansas School of Medicine
Kansas City, KS
Dermatologist
Adult & Pediatric Dermatology
Overland Park, Kansas

Michael J. Payette, MD, MBA, FAAD
Associate Professor of Dermatology
Associate Residency Director
University of Connecticut Health Center
Farmington, CT
Dermatologist and Partner
Central Connecticut Dermatology
Cromwell, CT

Introduction

Generalized pustular psoriasis (GPP) is a variant of pustular psoriasis that presents with acute or chronic episodes of sterile pustules and generalized erythema.^1-4 The onset of GPP is typically “extraordinarily severe,” according to Dr Chovatiya. Its clinical course may involve relapse with recurrent flares or persistence with intermittent flares. The flares are typically idiopathic; however, potential flare triggers include certain medications, viral infections, sunburn, stress, and menstruation.³ GPP can also be accompanied by symptoms of systemic illness (eg, pain, fever, fatigue), arthritis, neutrophilic cholangitis, and severe organ dysfunction. In rare cases, it may lead to death, which is typically due to associated septic shock and cardiorespiratory failure.^1,3,4

The risk of hospitalization and/or death associated with GPP can lead to patients living in considerable fear, shared Dr Chovatiya. Describing the patient experience, Dr Kaplan said, “They feel like they have more than just a flu-like illness….They feel like they’re going to die.” The cutaneous manifestations of the disease can also have a negative effect on daily life. “This disease has a lot of personal, emotional, and physical implications on a patient,” said
Dr Payette. “Oftentimes, these folks have plaques that are either itchy or painful. They can shed scale when they’re walking or when they’re scratching. And if involvement occurs in certain specific body areas, it can have a huge impact on [a patient’s] interpersonal relationships.”

GPP is a rare orphan disease. “Many dermatologists may only encounter a handful of cases during their entire career,” said Dr Payette. Most patients who develop GPP previously were diagnosed with psoriasis vulgaris.⁵ The low incidence of GPP combined with limited knowledge of disease pathogenesis has contributed to challenges with treatment. There has also been a lack of quality data on available therapeutics and no standardized approach to monitoring response to therapy.² “There is no current standard of care for somebody who comes in with GPP,” said Dr Kaplan. “It’s a more neutrophil-driven disease, so it’s approached a little bit differently than [is] regular psoriasis…regular psoriasis is an IL (interleukin)-17– and IL-23–promoted disease; GPP is [promoted by] IL-1 and IL-36.”⁵

Until recently, there were no FDA-approved therapies to treat GPP. In 2022, an injectable formulation of the IL-36R antagonist spesolimab-sbzo was approved for the treatment of GPP flares in adults.^4,6

GPP Pathogenesis

The pathogenesis of GPP is not fully known, and it varies based on whether it presents alone or with previous or current psoriasis vulgaris.³ Exploring the pathological differences between GPP disease states is important, shared Dr Chovatiya, because it helps to guide the development of targeted therapies. Cases of GPP alone most often are caused by recessive mutations of the IL36RN gene; these mutations can be homozygous, compound heterozygous, or single heterozygous in nature. IL36RN promotes inflammation by encoding the IL-36R antagonist, which, in turn, antagonizes the cytokines IL-1F6, IL-1F8, and IL-1F9 involved in proinflammatory signaling pathways. An IL36RN mutation causes these cytokines to lose inhibition and leads to subsequent inflammation.^3,5

There are no clear differences between phenotypes that have the IL36RN mutation vs those that do not; however, it is possible that IL36RN mutations are associated with earlier onset of GPP and higher risk for systemic inflammation. The potential presence of an unapparent IL36RN mutation necessitates genetic testing to identify IL36RN status and to guide treatment decisions.³

Diagnostic Considerations

Because GPP can be a life-threatening condition, “it is important to make the diagnosis quickly and intervene quickly,” said Dr Payette. However, the rarity of GPP can make its diagnosis challenging. Dr Kaplan said, “It’s usually lower on the differential when you see somebody who comes in with an erythrodermic eruption with or without sterile pustules.” The number of conditions considered in a GPP differential diagnosis is substantial. Most notably, acute generalized exanthematous pustulosis—which typically presents with a more rapid onset and resolution than that of GPP and is often triggered by use of antibiotics—should be considered.³

The diagnostic assessment for GPP should involve a full work-up, shared Dr Kaplan, including patient history, physical examination, drug exposure, and travel history. Diagnostic tests include basic bloodwork (complete blood count and chemistry panel), skin biopsies, and immunofluorescence. In the presence of GPP, abnormal laboratory values may include left shift leukocytosis; a high erythrocyte sedimentation rate; elevated C-reactive protein, antistreptolysin O antibody, and immunoglobulin (Ig) -G or IgA levels; hypoproteinemia; or hypocalcemia. Additional diagnostic criteria are histopathological confirmation of spongiform pustules of Kogoj, fever and other systemic symptoms, and sterile pustules found across erythematous skin.^3,7 “The pustules are going to be one of the key features in the clinical diagnosis of this disease,” said Dr Kaplan. He also noted that fever and a toxic appearance usually are present; this requires differential diagnosis to rule out infection.

Measuring disease severity

To measure the severity of GPP, available tools include the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA), the Generalized Pustular Psoriasis Area and Severity Index (GPPASI), and the modified Japanese Dermatological Association Severity Index (JDA-SI).^4,8 The GPPGA establishes subscores for 3 individual symptoms (erythema, pustules, and scaling) and a final score that combines the 3 subscores. The scoring scale ranges from 0 to 4, with “0” meaning clear, “1” meaning almost clear (including no fever), “2” meaning mild, “3” meaning moderate, and “4” meaning severe with “fiery red” erythema, dense pustules with pustular lake, and extreme scaling or crusting that cover nearly all or all lesions.⁴ Similarly, the GPPASI score assesses the severity of erythema, pustules, and scaling (on a range of 0 [no disease] to 4 [most severe]); it combines that score with a calculation of skin surface area involvement to determine scoring for the overall GPP disease state (range, 0-72).⁴ The JDA-SI, in addition to measuring skin lesions (erythema, pustules, edema), also assesses fever, white blood cell count, and C-reactive protein and serum albumin levels. The total score ranges from 0 to 17, with 17 indicating most severe disease.⁸

Treatment of GPP

The GPP treatment approach should involve both short- and long-term therapeutic management strategies and shared decision-making with the patient to address quality of life concerns.⁹ During a GPP flare, immediate effort should be made to alleviate cutaneous and systemic symptoms. Of note, it is possible to control cutaneous symptoms within a week of initiating IL-36R–targeted therapy.^4,9 Initial treatment of GPP flares should also involve efforts to reduce risk of complications (eg, severe infection, heart or kidney failure, cardiovascular aseptic shock, neutrophilic cholangitis, uveitis, and acute respiratory distress syndrome).⁹ Long-term management should reduce the risk of future flares and address symptoms present between flares, which can be experienced by more than 80% of patients with GPP. Comorbidities (eg, hypertension, hyperlipidemia, and diabetes mellitus) should also be effectively managed.⁹

Standard therapies

Before the approval of spesolimab, there was limited evidence regarding therapies used to treat GPP.^2,5,9 In addition, available therapies were not targeted, which made treatment decisions tricky, according to Dr Chovatiya. He noted the need for quick and efficient targeted options for severe cases of GPP, “because we know that everything from sepsis to even end-stage organ damage can occur if we don’t get things taken care of fast enough.”

In 2011, the National Psoriasis Foundation (NPF) formed a consensus statement outlining treatments for GPP, emphasizing that treatment selection should be based on level of involvement and disease severity.² Many recommended therapies from 2011 continue to be mainstay treatment options, but they have considerable deficiencies.^2,9 Per the NPF consensus statement and based on limited data, the preferred first-line treatment for GPP is the retinoid acitretin.² However, use of acitretin has been associated with disease recurrence upon discontinuation and various adverse events (AEs), such as liver and skeletal toxicity, teratogenicity, and hyperlipidemia. Biological predictors of treatment efficacy vs risk are being investigated, and more studies are needed to determine reliable markers.⁹

Viable first-line alternatives to acitretin are cyclosporine and methotrexate.² In the real world, cyclosporine is likely the most broadly used, according to Dr Payette. “The advantage of cyclosporine is that it’s very fast,” he said. This can be particularly beneficial as first-line treatment for severe, acute disease. “However, this medicine can be very toxic to the body, and, in particular, it can cause changes in electrolytes, like magnesium. It can cause changes in uric acid level. It can cause hypertension, and it’s directly nephrotoxic to the kidney.…It’s not adequate for long-term use.” In addition, like acitretin, cyclosporine use often does not prevent disease recurrence.^2,9 Dr Payette stated that methotrexate therapy is slow acting (reaching an effective dose over several weeks) and not appropriate as a first-line treatment. Methotrexate-related AEs include liver toxicity, gastrointestinal symptoms, and infection.^2,9 The TNFα inhibitor infliximab, which is approved for the treatment of GPP in Japan, also is considered to be a first-line treatment, especially for patients with extensive disease.^2,9

Second-line treatments for GPP that are recommended by the 2011 NPF consensus statement include adalimumab, etanercept, combination therapy (typically, a first-line systemic agent plus a biologic medication), and psoralen plus ultraviolet A.² Topical therapies can be used with systemic therapy; in mild cases, they may be used in the first line. Efficacy has been shown in case reports for the topicals calcipotriol and tacrolimus.²

Treatment options for GPP broadened in 2022, when the FDA approved spesolimab as the first treatment indicated in the United States for GPP in adults.⁶ “We now have a blockbuster revolution in our ability to target this disease,” said Dr Chovatiya.

Spesolimab-sbzo injection

Spesolimab is a humanized monoclonal IgG1 antibody that binds to IL-36R, preventing its activation and the subsequent actions of proinflammatory pathways.⁶ It is an intravenous (IV) injection given via infusion over the course of 90 minutes.⁶ “Spesolimab can be administered as a one-time infusion, which can benefit management of this disease, even as fast as within the first 1 to 2 days,” said Dr Payette. “In some instances, patients do require a second infusion of spesolimab, but this represents the vast minority of those treated with this medication.” He added that the administration route should not be a barrier, because many offices either are associated with or have inhouse infusion centers. In addition, private infusion centers can be found across the country.

Approval of spesolimab for GPP was based on results from the phase 2, multicenter, randomized, placebo-controlled Effisayil 1 trial (NCT03782792).4 “[The results of] this clinical trial [have shown spesolimab use] to be a huge improvement in anything we’ve seen previously,” said Dr Kaplan. “Some of the early data [show] a very quick response.”

In the trial, 53 eligible patients (age, 18-75 years) had a diagnosis of moderate to severe GPP flare and any IL36RN mutation status. The term “moderate to severe” indicated flares with a GPPGA total score of 3 or more, a GPPGA pustulation subscore of 2 or more, pustules that were new or becoming worse, and erythema and pustules covering 5% or more of the body surface area. Patients were ineligible if they had plaque psoriasis either without pustules or with pustules present only in psoriasis plaques.⁴ The key primary end point of the trial was a GPPGA pustulation subscore of 0 (no evidence of pustules) at the end of week 1, and the key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear) at the end of week 1.⁴

On day 1, patients were randomly assigned 2:1 to receive either spesolimab 900 mg IV (n = 35) or placebo (n = 18); both patients and investigators were blinded at the first dose. On day 8, all patients with ongoing symptoms (GPPGA total and pustulation scores, ≥ 2) were eligible to receive open-label spesolimab 900 mg IV; after day 8, they could receive open-label spesolimab 900 mg IV as a rescue treatment to week 12. Eligible patients who completed the trial subsequently could enter a 5-year open-label extension study.⁴

Results demonstrated that 19 patients (54%) who received spesolimab experienced rapid and complete pustular clearance (GPPGA pustulation subscore, 0) by week 1 vs 1 patient (6%) who received placebo (difference, 49%; 95% CI, 21%-67%; P < .001).⁴ In addition, 15 patients (43%) in the spesolimab group and 2 patients (11%) in the placebo group experienced a total GPPGA score of 0 or 1 (clear or almost clear [difference, 32%; 95% CI, 2%-53%; P = .02)].⁴ Improvements from baseline in total GPPGA pustulation subscores and total GPPGA scores were sustained through week 12.⁴

During the first week, the most common AEs (≥ 5%) were weakness and fatigue, nausea and vomiting, headache, pruritis and prurigo, hematoma and bruising at the site of infusion, and urinary tract infection.⁶ In addition, 6% of patients in the spesolimab group and none in the placebo group experienced the following serious AEs: drug reaction with eosinophilia and systemic symptoms, urinary tract infection, drug-induced hepatic injury, and arthritis.⁴ At week 1, infection was experienced by 17% of those in the spesolimab group and 6% in the placebo group; at week 12, it was noted in 47.1% of those in the spesolimab group.⁴ Regarding the infection rate, Dr Kaplan said, “When you initiate treatment, patients are going to be at increased risk for infections over the next 4 months, give or take. So you’ll need to monitor them closely for that…most of [the infections] are mild and easily treated.” He added that detection of eosinophils would not be surprising. Of note, throughout the trial, there were no discontinuations due to AEs.⁴

An anti–IL-36R therapy in development

Imsidolimab, a monoclonal antibody that targets IL-36R, is currently under phase 3 investigation for the treatment of GPP.^8-11 Results on imsidolimab efficacy and safety for moderate to severe GPP from the phase 2, open-label GALLOP trial (NCT03619902) were previously presented during the European Academy of Dermatology and Venereology 2021 Congress on October 2, 2021.^8,10 Eight patients presented with either a GPPGA moderate severity score or a JDA-SI total score of at least 6, with pustules and erythema covering at least 10% of body surface area.^8,10 The trial involved treatment with imsidolimab 750 mg IV on day 1 and then imsidolimab 100 mg subcutaneously on days 29, 57, and 85. Rescue medication was available during this time.^8,10 A primary end point was the number of patients who experienced a clinical response determined by the Clinical Global Impression scale to be either “very much improved,” “much improved,” or “minimally improved”; this end point was based on a reduction in the modified JDA-SI total score at weeks 4 and 16.^8,10

Of the 8 patients treated with imsidolimab monotherapy, a “very much improved” and “much improved” status was noted in 6 patients (75%) by week 4 and by 5 patients (62%) by week 16 (95% CI, 35%-97% for both). Two patients missed a status check at both weeks 4 and 16; the 6 who were evaluated did not require rescue medication during the treatment period.¹⁰ The GPPGA was implemented after study initiation and used to assess 4 patients. Clear or almost clear status was achieved by 2 patients (50%; 95% CI, 7%-93%) at week 4 and 3 patients (75%; 95% CI, 19%-99%) at week 16.¹⁰ Regarding safety, 2 patients (25%) experienced serious AEs (ie, severe sepsis from a nosocomial infection, mild SARS-CoV-2 infection). Additional AEs potentially linked to treatment were nausea, oropharyngeal pain, psoriasis, and vomiting. None of the patients discontinued treatment due to treatment-related AEs.¹⁰ Promising results from the phase 2 trial led to the 2022 launch of the phase 3, multicenter, randomized, placebo-controlled GEMINI1 trial (NCT05352893) that is exploring imsidolimab efficacy and safety among adults with GPP. Patients currently are being recruited for this study.^10,11

Looking Ahead

Moving forward, the experts acknowledged the need for broad education efforts regarding GPP diagnosis and treatment across medical specialties. “Any time you have a disease that’s uncommon or rare, it’s important to educate as many people as possible so that it can be diagnosed readily, and treatment can be initiated in a timely manner,” said Dr Payette. “Because many dermatologists may not see GPP more than once in their career, the most important facet for our institution to educate is our up-and-coming dermatologists—namely, our dermatology residents.” He noted that targeting dermatology residents could help support them in making timely GPP diagnoses throughout their career, even if the disease rarely presents in their facilities. He emphasized that timely intervention is the most important consideration, because this disease can be life-threatening.

Education for clinicians could include components of an appropriate work-up, approaches to ensure accurate and timely diagnosis, and ways to initiate targeted treatment as quickly as possible. “This education doesn’t need to stay within dermatology,” said Dr Chovatiya. “It needs to expand to our other medical specialties, because individuals who have flares of GPP can oftentimes end up in acute care settings.” To support timely, early treatment, Dr Chovatiya recommended “getting spesolimab onboard…so, at the moment’s notice when someone starts developing that pustular eruption, you can really do a good job of delivering that medication.”He highlighted the robust spesolimab patient access program that supports connecting patients with the center that can administer the therapy as quickly as possible. “[Spesolimab] can be administered to individuals at the first signs or symptoms of disease, and [it does a good job] of abrogating flares, stopping disease progression, and turning things around in the right way. This is really a big deal for dermatology,” he said. “Spesolimab is the first IL-36R–block­ing medication that we have, and [it is] one of the best examples…of taking the bench to the bedside. That’s really incredible…because, sometimes, you don’t get those amazing home run stories. It is a game changer.”

References

1. Noe MH, Wan MT, Mostaghimi A, et al. Evaluation of a case series of patients with generalized pustular psoriasis in the United States. JAMA Dermatol. 2022;158(1):73-78. doi:10.1001/jamadermatol.2021.4640

2. Robinson A, Van Voorhees AS, Hsu S, et al. Treatment of pustular psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2012;67(2):279-288. doi:10.1016/j.jaad.2011.01.032

3. Hoegler KM, John AM, Handler MZ, Schwartz RA. Generalized pustular psoriasis: a review and update on treatment. J Eur Acad Dermatol Venereol. 2018;32(10):1645-1651. doi:10.1111/jdv.14949

4. Bachelez H, Choon SE, Marrakchi S, et al; Effisayil 1 Trial Investigators. Trial of spesolimab for generalized pustular psoriasis. N Engl J Med. 2021;385(26):2431-2440. doi:10.1056/NEJMoa2111563

5. Kearns DG, Chat VS, Zang PD, Han G, Wu JJ. Review of treatments for generalized pustular psoriasis. J Dermatolog Treat. 2021;32(5):492-494. doi:10.1080/09546634.2019.1682502

6. Spevigo. Prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc; 2022. Accessed March 19, 2023. https://content.boehringer-ingelheim.com/DAM/18918a08-b1a0-44f0-8f01-af1e01236719/spevigo-us-pi.pdf

7. Umezawa Y, Ozawa A, Kawasima T, et al. Therapeutic guidelines for the treatment of generalized pustular psoriasis (GPP) based on a proposed classification of disease severity. Arch Dermatol Res. 2003;295(suppl 1):S43-S54. doi:10.1007/s00403-002-0371-6

8. A study to evaluate the efficacy and safety of imsidolimab (ANB019) in adults with generalized pustular psoriasis (GPP). ClinicalTrials.gov. Updated March 29, 2022. Accessed March 19, 2023. https://clinicaltrials.gov/ct2/show/NCT03619902

9. Krueger J, Puig L, Thaçi D. Treatment options and goals for patients with generalized pustular psoriasis. Am J Clin Dermatol. 2022;23(suppl 1):51-64. doi:10.1007/s40257-021-00658-9

10. Gudjonsson JE, Reich A, Barker J, et al. Imsidolimab, an anti-IL-36 receptor monoclonal antibody, in the treatment of generalized pustular psoriasis: results from a phase 2 trial. Presented at the European Academy of Dermatology and Venerology 30th Congress; September 29 to October 2, 2021; Virtual. Anaptysbio. Accessed March 19, 2023. https://www.anaptysbio.com/wp-content/uploads/EADV-2021_ABSID_678_20210824.final_.sent_.pdf

11. Study to evaluate the efficacy and safety of imsidolimab (ANB019) in the treatment of subjects with GPP (GEMINI1). ClinicalTrials.gov. Updated May 5, 2022. Accessed March 19, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05352893