Clinical Review

Generalized Pustular Psoriasis: A Review of the Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment

Cutis. 2022 August;110(2S):19-25 | doi:10.12788/cutis.0579

Kelly A. Reynolds, MD

Deeti J. Pithadia, MD

Erica B. Lee, MD

Dillon Clarey, MD

Wilson Liao, MD

Jashin J. Wu, MD

Generalized pustular psoriasis (GPP) is a rare severe variant of psoriasis that is characterized by the abrupt widespread onset of small pustules accompanied by systemic manifestations of inflammation. It can arise in patients with a history of psoriasis as well as in those without, sometimes due to medication initiation or withdrawal, pregnancy, or infection. Generalized pustular psoriasis is thought to be driven primarily by innate immunity and unrestrained IL-36 cytokine activity. Recent genetic analyses have identified 3 genetic mutations that are associated with GPP—IL36RN, CARD14, and AP1S3—though these mutations only account for a minority of cases. There are many cutaneous pustular diseases that must be ruled out in the evaluation of a patient with suspected GPP, especially acute generalized exanthematous pustulosis (AGEP), and histologic analysis is the cornerstone of diagnosis. Although the quality of evidence to generate treatment recommendations for GPP is limited, management often includes utilization of systemic agents and/or biologics, usually with adjunctive topical treatment. Accumulating evidence suggests that biologic agents, especially infliximab, may be considered as first-line treatment of GPP, especially in severe acute cases, due to their abrupt onset of action and favorable side-effect profiles compared with oral systemic agents.

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Practice Points

Generalized pustular psoriasis (GPP) is a rare severe variant of psoriasis that is characterized by the abrupt widespread onset of small pustules.
Although no treatments have specifically been approved for GPP, various biologics, especially infliximab, may be effective in achieving rapid clearance in patients with GPP. Other oral systemic agents including acitretin, cyclosporine, and methotrexate also have been shown to be effective.

References

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Acute generalized pustular psoriasis (GPP) is a rare severe variant of psoriasis characterized by the sudden widespread eruption of sterile pustules.^1,2 The cutaneous manifestations of GPP also may be accompanied by signs of systemic inflammation, including fever, malaise, and leukocytosis.² Complications are common and may be life-threatening, especially in older patients with comorbid diseases.³ Generalized pustular psoriasis most commonly occurs in patients with a preceding history of psoriasis, but it also may occur de novo.⁴ Generalized pustular psoriasis is associated with notable morbidity and mortality, and relapses are common.^3,4 Many triggers of GPP have been identified, including initiation and withdrawal of various medications, infections, pregnancy, and other conditions.^5,6 Although GPP most often occurs in adults, it also may arise in children and infants.³ In pregnancy, GPP is referred to as impetigo herpetiformis, despite having no etiologic ties with either herpes simplex virus or staphylococcal or streptococcal infection. Impetigo herpetiformis is considered one of the most dangerous dermatoses of pregnancy because of high rates of associated maternal and fetal morbidity.^6,7

Acute GPP has proven to be a challenging disease to treat due to the rarity and relapsing-remitting nature of the disease; additionally, there are relatively few randomized controlled trials investigating the efficacy and safety of treatments for GPP. This review summarizes the features of GPP, including the pathophysiology of the disease, clinical and histological manifestations, and recommendations for management based on a PubMed search of articles indexed for MEDLINE using MeSH terms pertaining to the disease, including generalized pustular psoriasis, impetigo herpetiformis, and von Zumbusch psoriasis.

Pathophysiology

The pathophysiology of GPP is only partially understood, but it is thought to have a distinct pattern of immune activation compared with plaque psoriasis.⁸ Although there is a considerable amount of overlap and cross-talk among cytokine pathways, GPP generally is driven by innate immunity and unrestrained IL-36 cytokine activity. In contrast, adaptive immune responses—namely the tumor necrosis factor (TNF) α, IL-23, IL-17, and IL-22 axes—underlie plaque psoriasis.^8-10

Proinflammatory IL-36 cytokines α, β, and γ, which are all part of the IL-1 superfamily, bind to the IL-36 receptor (IL-36R) to recruit and activate immune cells via various mediators, including IL-1β; IL-8; and chemokines CXCL1, CXCL2, and CXCL8.³ The IL-36 receptor antagonist (IL-36ra) acts to inhibit this inflammatory cascade.^3,8 Microarray analyses of skin biopsy samples have shown that overexpression of IL-17A, TNF-α, IL-1, and IL-36 are seen in both GPP and plaque psoriasis lesions, but GPP lesions had higher expression of IL-1β, IL-36α, and IL-36γ and elevated neutrophil chemokines—CXCL1, CXCL2, and CXCL8—compared with plaque psoriasis lesions.⁸

Gene Mutations Associated With GPP

There are 3 gene mutations that have been associated with pustular variants of psoriasis, though these mutations account for a minority of cases of GPP.⁴ Genetic screenings are not routinely indicated in patients with GPP, but they may be warranted in severe cases when a familial pattern of inheritance is suspected.⁴

IL36RN—The gene IL36RN codes the anti-inflammatory IL-36ra. Loss-of-function mutations in IL36RN lead to impairment of IL-36ra and consequently hyperactivity of the proinflammatory responses triggered by IL-36.³ Homozygous and heterozygous mutations in IL36RN have been observed in both familial and sporadic cases of GPP.^11-13 Subsequent retrospective analyses have identified the presence of IL36RN mutations in patients with GPP with frequencies ranging from 23% to 37%.^14-17IL36RN mutations are thought to be more common in patients without concomitant plaque psoriasis and have been associated with severe disease and early disease onset.¹⁵

CARD14—A gain-of-function mutation in CARD14 results in overactivation of the proinflammatory nuclear factor κB pathway and has been implicated in cases of GPP with concurrent psoriasis vulgaris. Interestingly, this may suggest distinct etiologies underlying GPP de novo and GPP in patients with a history of psoriasis.^18,19

Generalized Pustular Psoriasis: A Review of the Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment

References

Pathophysiology

Gene Mutations Associated With GPP

Pages

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