Understanding Generalized Pustular Psoriasis

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In this interview, Dr Jason Ezra Hawkes discusses generalized pustular psoriasis (GPP), a rare psoriasis variant. GPP is characterized by acute onset of widespread pustules and erythema. The IL-36 pathway plays a key role in GPP development, and gene mutations impact this pathway. Physicians should be cautious of diagnostic delays because GPP can be mistaken for infections or other pustular psoriasis types. Dr Hawkes emphasizes the need to educate dermatologists about psoriasis variants for better patient care.

The Dermatologist: Can you explain how GPP is characterized by the acute onset of diffuse superficial pustules on the skin?

Dr Hawkes: Psoriasis is a heterogeneous, T cell-mediated, inflammatory condition with multiple clinical subtypes or variants. While many providers might be familiar with plaque psoriasis, the classical form of this disease, which represents approximately 85% of cases, the less common variants often go undiagnosed or misdiagnosed for many years. GPP is one of those psoriasis clinical variants.

GPP is a distinct clinical entity that is characterized by the recurrent, cyclic formation of widespread sterile pustules, erythema, and desquamation. Many patients have systemic symptoms that may accompany these acute flares, including fever, malaise, joint inflammation, or skin pain. While GPP can occur concomitantly with plaque psoriasis, this severe form of psoriasis is often the first and only manifestation of psoriatic disease in an affected individual. Untreated GPP can result in serious consequences for patients, such as secondary organ failure, increased risk of infection, and even death.

The Dermatologist: Your recent publication noted that, “The IL-36 pathway plays a central role in the development of GPP, although several other genes may be associated.” What other genes are associated with GPP and how do they work?

Dr Hawkes: For plaque psoriasis and many of the other psoriasis variants, increased IL-23 and IL-17 signaling represent the pre-dominant cytokines driving disease pathogenesis. Dysregulation of the IL-23/17 axis has a profound pro-inflammatory effect on the immune system and skin, resulting in the hyperproliferation of epidermal keratinocytes. In response to this pro-inflammatory environment, epidermal keratinocytes begin to upregulate and secrete several proteins and cytokines that further modulate the immune response, recruit other immune cells, and sustain chronic plaque formation. These keratinocyte-derived signals include chemokines, S100 proteins or antimicrobial peptides, IL-19, IL-17C, and IL-36, which work in concert or synergistically with increased IL-23 and IL-17 cytokines. The overwhelming majority of gene mutations associated with plaque psoriasis impact, in some way or another, the primary immune signals we typically associate with psoriasis pathogenesis.

In contrast to plaque psoriasis, IL-36 signaling is the predominant signaling pathway driving GPP. IL-36 signaling is critical to our innate or rapid immune response and plays a central role in the recruitment of neutrophils, which form the cellular makeup of a sterile pustule. The IL-36 family consists of several agonists (IL- 36α, IL 36β, IL 36γ) and an IL-36 receptor antagonist (IL-36Ra) to modulate IL-36 signaling. The immunopathogenesis of GPP is the result of increased or unopposed IL-36 signaling due to increased IL-36 agonists and/or ineffective inhibition via IL-36Ra. Fittingly, the gene mutations most strongly associated with GPP are those that result in dysregulated IL-36 signaling such as IL36RN gene mutations, which impair the normal inhibitory function of the IL- 36R antagonist.

IL36RN mutations are significantly enriched in patients with GPP compared with plaque psoriasis and correlate with an earlier onset and a more severe clinical form of the disease. Interestingly, IL36RN mutations are more commonly found in patients who only have GPP vs those individuals who have both GPP and plaque psoriasis. This provides further support for the distinct immunopathogenesis of these 2 psoriasis subtypes. Several other gene mutations have been identified in GPP pedigrees, including CARD14, AP1S3, TNIP1, SERPINA3, and MPO. Mutations in these other GPP-associated genes drive pustular disease via a variety of immune mechanisms that promote dysregulated IL-36 signaling, including altered NF-κB signaling, vesicular trafficking in keratinocytes, and regulation of neutrophil proteases.

The Dermatologist: How is GPP often mistaken for an infectious condition or other types of pustular psoriasis?

Dr Hawkes: As mentioned earlier, the clinical manifestations of GPP are primarily the presence of pustules, erythema, and desquamation with or without the presence of systemic symptoms. Unfortunately, these clinical manifestations are not necessarily specific and may be the result of a nonpsoriasis etiology, such as a primary infection; a drug reaction such as acute generalized exanthematous pustulosis or AGEP; or other neutrophilic or pustular conditions, such as subcorneal pustular dermatosis, also known as Sneddon-Wilkinson disease.

The nonspecific cutaneous manifestations of GPP may result in diagnostic or treatment delays. Nondermatology providers in acute hospital or outpatient clinic settings often never consider GPP in their differential diagnosis due to the rarity of the condition. This has horrendous consequences for patients living with GPP, who are frequently left suffering from their disease symptoms while they cycle through many ineffective antibiotic or anti-inflammatory medications before eventually finding a provider who can diagnose and manage their psoriatic disease. Several studies suggest that patients living with GPP can go undiagnosed or undertreated for many years before receiving GPP-appropriate treatments.

The Dermatologist: What actions can physicians take to exclude these differential diagnoses?

Dr Hawkes: The initial evaluation and workup of a GPP patient is very important. A detailed patient history, careful review of recent and current medications, and a thorough skin exam are essential to establishing a GPP diagnosis, which often takes longer than the usual 10- or 15-minute timeslot allocated for most routine dermatology appointments. Although we currently lack a single, specific test to diagnose GPP, several rapid tests are available to help exclude other possible disease mimics, such as skin or blood cultures to rule out a primary infection. Other lab tests, such as a complete blood cell count, complete metabolic panel, or C-reactive protein, may be appropriate in patients with severe disease or systemic symptoms. These tests can also be extremely useful in helping determine the appropriate triage or treatment setting (outpatient vs inpatient) for patients who present with acute GPP flares. A preexisting history of plaque psoriasis or positive family history of plaque or pustular disease is also important to collect.

It is important to note here that while a punch biopsy of involved skin can be useful for differentiating GPP from nonpsoriasis etiologies, such as a primary infection, drug reaction, or immunobullous disease, the processing of tissue specimens takes time, generally 5 to 10 days, and may result in a nondiagnostic or descriptive pathology result. For this reason, providers should not delay the initiation of appropriate GPP treatments for patients presenting with acute or severe GPP flares while laboratory and/or pathology tests are processing.

The Dermatologist: Are there any tips or insights you would like to share with your dermatologist colleagues regarding the diagnosis of GPP or other psoriasis variants?

Dr Hawkes: It is imperative that we educate our dermatology trainees and colleagues about the less common, nonplaque variants of psoriatic disease and how to recognize them. These variants include psoriatic arthritis and guttate, inverse, erythrodermic, and pustular forms of psoriasis. Further variation also exists within each subtype, such as restricted scalp or palmoplantar disease for patients with plaque psoriasis. We often lump all these disease subtypes together when we speak about “psoriasis” in general. This improper consolidation of the variants into the same bucket per se fails to convey the heterogeneity of psoriatic disease and the unique underlying immunology and genetic landscape of each subtype. Being more specific in our reference to psoriasis subtypes will become increasing more important with time since ongoing research and clinical trials are beginning to tease out the subtleties for each variant. This has resulted in the testing and approval of novel, selective immune therapies for the treatment of specific disease subtypes. Additionally, the US Food and Drug Administration (FDA) approval of medications is tied to an unambiguous psoriasis subtype, such as moderate to severe plaque psoriasis or psoriatic arthritis, forcing providers to specify the disease subtype in their clinical documentation to get insurance approval for virtually all psoriasis medications.

A prime example of this movement toward specificity is the development and recent FDA approval of spesolimab, a novel first-in-class humanized monoclonal immunoglobulin G1 antibody that binds to IL-36R and antagonizes IL-36 signaling for the treatment of acute GPP flares in adults. This is a critical step in medicine as we begin to approach more tailored or personalized treatment strategies. It is no longer appropriate to adopt treatment strategies that are essentially a “one-size-fits-all” approach as this is the antithesis of personalized care. Nevertheless, more research and clinical development are needed in this area of dermatology since many psoriasis subtypes lack even a single FDA-approved systemic medication, such as guttate, erythrodermic, or inverse psoriasis variants.

Reference

Bhutani T, Hawkes JE. Exploring the clinical features, immunopathogenesis and approach to diagnosis for generalized pustular psoriasis [podcast]. Clin Cosmet Investig Dermatol. 2023;16:1553-1558. doi:10.2147/CCID.S424073