Differentiating GPP From Plaque Psoriasis for Targeted Therapy

GPP
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While all types of psoriasis carry significant burdens of disease for patients, certain subtypes have more severe symptoms and require more urgency in diagnosis and treatment. Generalized pustular psoriasis (GPP) is one such subtype and may be considered a disease entity with a classification of its own.

GPP is characterized by widespread monomorphic pustules and erythema on the skin, rather than scaly plaques.1,2 It typically involves the rapid formation of sterile, pus-filled blisters or pustules on an erythematous background. It may present acutely and lead to systemic complications, including multisystem organ failure and death. Involvement is often much more widespread than plaque psoriasis, palmoplantar psoriasis, and acrodermatitis continua of Hallopeau (ACH), and it is often triggered by factors such as infections, stress, changes in medications, pregnancy, and environmental stimuli. Whereas plaque psoriasis predominantly involves the IL-23 and IL-17 pathways, IL-36 dysregulation is the predominant driver of GPP.1,3

Because the onset of GPP is typically so rapid and the symptoms so severe, accurate and prompt diagnosis and treatment are critical. However, diagnosis is often overlooked and delayed due in part to its rarity but also that rapid onset, as GPP patients often go to the emergency room instead of a dermatologist’s office. Unfortunately, this is also a function of lack of awareness both within and outside the dermatology community, and patients may need to carry their biopsy reports and notes with them once diagnosed for their continuity of care. Frequently, GPP is mistaken for skin infections or acute generalized exanthematous pustulosis (AGEP), and is treated with steroids and antibiotics. Educating primary care physicians and internists on GPP, therefore, is imperative.

THE IL-36 PATHWAY

Plaque psoriasis treatments can be just effective enough for GPP to deter physicians from taking the time to diagnose and specifically treat GPP. However, these treatments are typically only a temporary solution. When compared with the efficacy of targeting the IL-36 pathway, plaque psoriasis treatments are simply not the best option for the GPP patient.

A 2011 study of nine Tunisian multiplex families with autosomal recessive generalized pustular psoriasis showed inborn defects of the IL-36 pathway.4 Whereas IL-23 and IL-17 involve adaptive immune response, this study revealed that GPP involves an innate immune response. Patients with GPP typically have either higher levels of IL-36 or a defect in their IL-36 receptor antagonist, which shuts off the signaling of that pathway.1,3 Neutrophils are the primary histologic cell type in GPP and are activated largely via IL-36. This contributes to characteristic symptoms including severe desquamation and cutaneous pain. It is also a reason why GPP can be approached as an immunologically simpler disease than plaque-type psoriasis. As such, shutting down the predominant signaling driving this variant can be a very effective strategy for treatment.

EXPEDITIOUS TREATMENT

The success of GPP treatment is highly dependent on early intervention at flare onset. GPP progresses rapidly, and prompt evaluation by a dermatologist is essential. Untreated GPP can lead to secondary complications such as skin infections, sepsis, and secondary organ failure.2 GPP patients have been shown to have higher mortality rates than both the general population and patients with psoriasis vulgaris.5 A 2024 consensus paper stated that “GPP is a life-threatening disease that needs to be treated as quickly as possible.”6 The paper also noted that a skin biopsy is not necessary to make a clinical diagnosis of GPP.6 Similarly, tuberculosis screening is advised but should not delay the initiation of treatment. The paper also included a recommendation with high consensus that timely access to spesolimab, the first drug approved by the US Food and Drug Administration (FDA) for the treatment of GPP flares in adults, is critical to reducing morbidity and mortality.6

SPESOLIMAB

Spesolimab is a humanized, monoclonal antibody that binds specifically to the IL-36 receptor (IL-36R) and antagonizes IL-36 signaling.3 This type of therapy can mitigate flares and address flare prevention in GPP, presumably through rebalancing IL-36 signaling and modulating the pro-inflammatory response of the downstream effectors.3

Unlike plaque psoriasis, which is a T-cell-mediated disease, the primary cell type for GPP is the keratinocyte. Unlike plaque psoriasis, which is primarily T-cell–mediated, GPP is driven by keratinocytes. IL-36γ is the predominant driver of skin inflammation within these cells, and that can activate the pathway through the IL-36 receptor. An IL-36 receptor antagonist can stop that signaling. Whether a patient has a mutation that makes the IL-36 receptor protein dysfunctional, or their levels are simply too high despite a functioning break, blocking the receptor solves both problems. We are adding in and reinforcing the break of the system to shut off the feed-forward mechanism between the keratinocytes, IL-36, and the adaptive immune response. It is not an anti-cellular or cytotoxic therapy, and it does not suppress the activity of the dendritic cells.

GPP is a chronic disease, and it needs to be treated as such. As important as getting the patient through the flare is, the maintenance beyond that is equally critical. Plaque psoriasis treatments that block IL-23 or IL-17 are not sufficient. It is also important to remember that GPP patients rarely go from a flare to completely clear, and they typically have lingering skin pain, erythema, occasional pustules, and some scaling. IL-23 or IL-17 inhibition does not treat this as effectively as an IL-36 receptor antagonist does. These patients live in their own prison; very few diseases cause this level of anxiety and depression.

In the rare cases when patients who have had plaque psoriasis in the past develop GPP, it may be tempting to use only one drug. The patient may struggle to understand the concept of a drug working well for their plaque psoriasis but not for GPP. Still, plaque psoriasis treatments are unlikely to stop the skin pain, desquamation, burning, and stinging that GPP causes even after flares are resolved.

IN PRACTICE

When a patient is referred to a dermatologist with possible GPP, diagnosis confirmation is the priority. Next, securing spesolimab involves additional discussions and conversations with the pharmacy.

The first dose of spesolimab typically will be administered intravenously in the hospital. Following this, the patient should be evaluated for potential hemodynamic instability, elevated creatinine levels, high white blood cell counts, and signs of infection requiring longer hospital stay. Many patients can be discharged when the flares resolve.

Some patients require a second IV dose upon 1-week follow-up, so collaborating with an infusion center is important. After 1 month, the patient should begin a subcutaneous formulation of spesolimab. Moving forward, the patient also should keep a copy of their biopsy report in case they need to confirm their diagnosis with another clinician.

With appropriate care, most GPP patients can remain flare-free. High-dose spesolimab has demonstrated significant superiority to placebo in time-to-GPP flare (HR=0.16; 95% CI 0.05 to 0.54; P=0.0005) over 48 weeks in a phase 2b trial.7 As we enter the era of personalized medicine, GPP exemplifies the value of recognizing and targeting a specific pathway can turn a devastating disease into one that can be managed well. These are not patients we see often, but the impact we can make on their lives can be transformative. 

1. Torres T, Antunes J, et al. Update on generalized pustular psoriasis. Acta Med Port. 2025;38(5):321-330. doi:10.20344/amp.22672

2. Garg A, Noe MH, et al. Development of the Generalized Pustular Psoriasis Clinical Assessment Tool. J Am Acad Dermatol. 2024;90(1):192-195.

3. Hawkes JE, Visvanathan S, Krueger JG. The role of the interleukin-36 axis in generalized pustular psoriasis: a review of the mechanism of action of spesolimab. Front Immunol. 2023;14:1292941. doi:10.3389/fimmu.2023.1292941

4. Marrakchi S, Guigue P, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med. 2011;365(7):620-628. doi:10.1056/NEJMoa1013068

5. Ericson O, Löfvendahl S, Norlin JM, Gyllensvärd H, Schmitt-Egenolf M. Mortality in generalized pustular psoriasis: a population-based national register study. J Am Acad Dermatol. 2023;89(3):616-619. doi:10.1016/j.jaad.2023.04.066

6. Armstrong AW, Elston CA, et al. Generalized pustular psoriasis: a consensus statement from the National Psoriasis Foundation. J Am Acad Dermatol. 2024;90(4):727-730. doi:10.1016/j.jaad.2023.09.080

7. Morita A, Strober B, et al. Efficacy and safety of subcutaneous spesolimab for the prevention of generalised pustular psoriasis flares (Effisayil 2): an international, multicentre, randomised, placebo-controlled trial. Lancet. 2023;402(10412):1541-1551. doi:10.1016/S0140-6736(23)01378-8

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