Generalized Pustular Psoriasis (GPP)

Generalized pustular psoriasis (GPP) is a rare, severe, autoinflammatory form of psoriasis that affects multiple organ systems. This neutrophilic condition is characterized by widespread eruptions of pustules on inflamed skin that are often accompanied by constitutional symptoms such as fever.¹

The pathophysiological processes that occur during an acute flare of GPP can lead not only to the development of inflammation and cutaneous features but also to the activation and progression of severe disease-related complications, including hypothermia, infection, septic shock, cardiac or renal failure, acute respiratory distress syndrome, liver disease, and capillary leak syndrome.²

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Pathophysiological Processes of GPP

Both environmental exposures and genetics play a role in the pathogenesis of GPP. These factors can initiate several immunogenetic alterations that lead to the varying manifestations of GPP.³

Autoinflammatory Processes

Autoinflammatory processes that occur in GPP are caused by alterations in the innate immune system, inducing tissue damage in the absence of infection. Dysregulation of cytokine signaling or expression may trigger autoinflammatory processes.³

Autoinflammation inherently differs from autoimmunity because autoinflammation results from disruption of the innate immune system, whereas autoimmunity results from changes to adaptive immune system responses involving T or B cells.³

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Neutrophilic Infiltration

Neutrophils are components of the innate immune system that have been associated with psoriasis. Neutrophils induce oxidative stress, degranulation, and the formation of neutrophil extracellular traps (NETs).³

GPP is a neutrophilic-dominant form of psoriasis caused by episodic neutrophilic infiltration into the skin. These neutrophil infiltrates increase expression of neutrophil chemokines, such as CXCL1, CXCL2, and CXCL8.³ These chemokines attract other immune cells to these sites of inflammation to further promote the immune response, which in turn increases inflammation.⁴

IL-1/IL-36 Chemokine-Neutrophil Axis

Transcriptomic profiling has pointed to the significant relationship of the IL-1/IL-36 immune pathway along with neutrophilic infiltration in the pathogenesis of GPP. Both patients with GPP and plaque psoriasis demonstrate increased expression of IL-1, IL-36, IL-17a, tumor necrosis factor (TNF), and type II interferon; however, GPP skin lesions exhibit approximately ten times higher concentrations of IL-1 and IL-36 and decreased concentrations of IL-17a compared to plaque psoriasis lesions alone. This supports the notion that GPP pathophysiological processes shift away from autoimmune adaptive immune system responses and toward heavier innate immune system responses.^3,5

Mutations in various genes result in changes in protein expression and increased IL-36 cytokine activation.^3,5 Increased IL-36 cytokine activation in skin keratinocytes leads to promotion of a positive feedback loop that increases production of inflammatory molecules, including IL-36, neutrophil chemokines like CXCL1, CXCL2, and CXCL8, and other cytokines.^3,6

Neutrophil NETs correspondingly can activate IL-36 cytokines. This bidirectional inflammatory process occurs in the upper spinous layer close to neutrophil skin micro abscesses.^3,5

In ILIF5 knockout murine studies, overactivation of IL-36 signaling results in inflammatory and pustular skin lesions, further supporting the role of the IL-36 pathway in the pathogenesis of GPP and cutaneous pustular symptoms.^3,7

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Associated Genetic Mutations

Mutations in several genes in patients with GPP have confirmed the key role that IL-36 signaling plays in disease pathogenesis.³ These genes include IL36RN, CARD14, AP1S3, MPO, SERPINA1, SERPINA3, and TNIP1.^3,8

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Variations in gene mutations, dosage of mutant alleles, incomplete penetrance, and concurrent mutations in multiple genes all may influence clinical phenotype (or GPP subtype), age of onset, and severity of disease manifestations.^3,8

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References

1. Marrakchi S, Puig L. Pathophysiology of generalized pustular psoriasis. Am J Clin Dermatol. 2022 Jan;23(Suppl 1):13-19. doi:10.1007/s40257-021-00655-y
2.  Choon SE, Elewski BE, Fujita H, et al. Diversity in the clinical presentation of generalized pustular psoriasis (GPP): A series of case vignettes from around the world. Experimental Dermatology. 2023. doi:10.1111/exd.14794
3.  Young KZ, Sarkar MK, Gudjonsson JE. Pathophysiology of generalized pustular psoriasis. Exp Dermatol. 2023 Feb 13. Published online ahead of print. doi:10.1111/exd.14768
4. Chemokine. Britannica. Accessed June 30, 2023.
5. Johnston A, Xing X, Wolterink L, et al. IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis. J Allergy Clin Immunol. 2017;140(1):109-120. doi:10.1016/j.jaci.2016.08.056
6. Uppala R, Tsoi LC, Harms PW, et al. “Autoinflammatory psoriasis- ”genetics and biology of pustular psoriasis. Cell Mol Immunol. 2021;18(2):307-317. doi:10.1038/s41423-020-0519-3
7. Onoufriadis A, Simpson MA, Pink AE, et al. Mutations in IL36RN/ IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet. 2011;89(3):432-437. doi:10.1016/j.ajhg.2011.07.022
8. 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):1- 12. doi:10.3892/ijmm.2021.4951

Reviewed by Debjyoti Talukdar, MD, on 5/31/2023.

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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.