Generalized Pustular Psoriasis (GPP)

Generalized pustular psoriasis (GPP) is a rare, severe, autoinflammatory form of psoriasis that affects multiple organ systems in addition to the skin. The hallmark characteristic of GPP is the recurrence of widespread eruptions of pus-filled blisters on inflamed, erythematous skin. The dermatological episodes have an acute onset and are often accompanied by constitutional symptoms indicative of systemic inflammation, including high fever.¹

GPP is a neutrophilic disorder marked by autoinflammation of the innate immune system. It can co-occur with psoriasis vulgaris (plaque psoriasis), which is caused by dysregulation of the innate and adaptive immune systems and is considered an autoimmune disease.² 

Different cytokine pathways are involved in the 2 disorders. The interleukin 23 (IL-23)/IL-17 pathway contributes to the development of plaque psoriasis, whereas the IL-36 pathway is a central pathogenic component in GPP.²

A combination of environmental triggers and genetic mutations leads to the development of GPP. Researchers have identified several genes with mutations that contribute to the development of GPP, including IL36RN, CARD14, AP1S3, MPO, and SERPINA3.²

IL36RN

Research suggests that IL36RN mutations cause a specific subtype of GPP that manifests in isolation rather than concomitantly with psoriasis vulgaris. This subtype is also called deficiency of the IL-36 receptor antagonist (DITRA).³ 

IL-36 cytokines are classified within the IL-1 family and play a key role in regulating inflammatory cascades. The IL36RN gene encodes the IL-36 receptor antagonist, which blocks the receptors where 3 IL-1 family cytokines — IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36ϒ (IL-1F9) — bind to activate 2 proinflammatory signaling pathways, the nuclear factor kappa B (NFκB) pathway and the mitogen-activated protein (MAP) kinase pathway.⁴ 

Mutations in the IL36RN gene result in insufficient production of the IL-36 receptor antagonist, leading to the uncontrolled activation of inflammatory signaling pathways and excess production of proinflammatory cytokines.^2,3 The proinflammatory cytokines are active predominantly in epithelial tissues in the skin, trachea, and esophagus.⁴ 

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CARD14

Whereas IL36RN mutations prevent adequate blocking of inflammatory pathways, CARD14 mutations contribute to excessive activation of inflammatory signaling pathways.⁵ De novo missense CARD14 mutations contribute to a childhood form of GPP called CARD14-mediated pustular psoriasis (CAMPS). The mutations result in upregulation of the NFκB signaling pathway, which leads to the increased synthesis of chemokines and cytokines, including IL-8, IL-36, and CCL20, that cause psoriasis.³

CARD14 mutations often are seen in forms of GPP that co-occur with psoriasis vulgaris but rarely appear in subtypes of isolated GPP. The genomic structure of GPP-related genes shows that IL-36R binding site is usually affected after nucleotide substitution in exons of patients with GPP and psoriasis vulgaris who have CARD14 mutations.¹ 

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AP1S3

GPP pathogenic variants of AP1S3 appear mainly among people of European origin as opposed to those of Asian background. The c.338C>T substitution is more common among them. The variant frequency of AP1S3 in European GPP patients is around 10.8%.¹ 

AP1S3 encodes the adaptor protein complex 1 (AP-1), which promotes vesicular trafficking between the trans-Golgi network and endosomes. Changes to the genetic code in AP1S3 result in destabilization and deficiency of the AP-1 complex in skin keratinocytes, which then disrupt endosomal translocation of the innate pattern recognition Toll-like receptor 3 (TLR-3). These vesicular trafficking defects reduce TLR-3 signaling, resulting in severe skin inflammation.⁶

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MPO

Loss-of-function mutations in the myeloperoxidase (MPO) gene contribute to the development of GPP and increased neutrophil counts. MPO mutations appear to promote neutrophil survival by reducing the number of cells involved in neutrophil apoptosis. This process correlates directly with the neutrophilia seen during GPP flares.⁷

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SERPINA3

SERPINA3 encodes alpha-1-antichymotrypsin, a protein that inhibits cathepsin G, a protease secreted by neutrophils. Cathepsin G cleaves and therefore activates IL-36 precursors, contributing to activation of the proinflammatory signaling pathway. In patients with GPP who have SERPINA3 mutations, the proliferation of IL-36 agonists contributes to severe autoinflammation.²

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Environmental Triggers for Genetic GPP

Patients with the genetic variants described above are susceptible to the development of GPP when they are exposed to environmental triggers that activate the innate immune system and inflammatory signaling cascade. Such activation can cause life-threatening complications due to multiple organ system dysfunction.² 

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References

1. Zhou J, Luo Q, Cheng Y, Wen X, Liu J. An update on genetic basis of generalized pustular psoriasis (review). Int J Mol Med. 2021;47(6):118. doi:10.3892/ijmm.2021.4951
2. Marrakchi S, Puig L. Pathophysiology of generalized pustular psoriasis. Am J Clin Dermatol. 2022;23(Suppl 1):13-19. doi:10.1007/s40257-021-00655-y
3. Naik HB, Cowen EW. Autoinflammatory pustular neutrophilic diseases. Dermatol Clin. 2013;31(3):405-425. doi:10.1016/j.det.2013.04.001
4. Marrakchi S, Guigue P, Renshaw BR, 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. Generalized pustular psoriasis. MedlinePlus. Accessed May 25, 2023.
6. Setta-Kaffetzi N, Simpson MA, Navarini AA, et al. AP1S3 mutations are associated with pustular psoriasis and impaired toll-like receptor 3 trafficking. Am J Hum Genet. 2014;94(5):790-797. doi:10.1016/j.ajhg.2014.04.005
7. Vergnano M, Mockenhaupt M, Benzian-Olsson N, et al. Loss-of-function myeloperoxidase mutations are associated with increased neutrophil counts and pustular skin disease. Am J Hum Genet. 2020;107(3):539-543. doi:10.1016/j.ajhg.2020.06.020

Reviewed by Debjyoti Talukdar, MD, on 6/29/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.