Generalized Pustular Psoriasis

Etiology

Pustular psoriasis occurs in genetically susceptible individuals and may be precipitated by multiple risk factors, resulting in psoriasiform changes and marked neutrophilic accumulation within the epidermis. An increased frequency of the human leukocyte antigen B27 (HLA-B27) allele has been reported among patients with pustular psoriasis compared with the general population. Most cases are idiopathic. However, several factors have been implicated in disease onset or exacerbation.

Infectious triggers, particularly bacterial and viral pathogens, are commonly reported. Staphylococcus aureus and Streptococcus epidermidis have been associated with disease exacerbation.[4] Viral infections, including influenza, have also been reported to precipitate generalized pustular psoriasis (GPP), and acute exacerbations associated with respiratory syncytial virus infection have been described.[5] Hypocalcemia may develop as a consequence of GPP or serve as a precipitating factor, particularly in the setting of hypoparathyroidism.[6]

Abrupt withdrawal of systemic corticosteroids and the use of potent topical corticosteroids under occlusion have been associated with the onset of pustular psoriasis.[7][8] Disease flares following cyclosporine withdrawal have also been reported.[9] Additional medications occasionally implicated in pustular psoriasis include terbinafine, propranolol, bupropion, lithium, phenylbutazone, salicylates, and potassium iodide. Topical therapies, such as coal tar and dithranol, may precipitate pustulation when applied inappropriately during unstable disease.[10]

Pregnancy-associated pustular psoriasis, historically termed "impetigo herpetiformis," is a distinct subtype associated with an increased risk of stillbirth and fetal anomalies.[11] A subset of patients with pustular psoriasis exhibits features of autoinflammatory disease associated with specific genetic mutations. Identified syndromes include deficiency of the IL-36 receptor antagonist (DITRA) and deficiency of the IL-1 receptor antagonist (DIRA).

Phototherapy has also been reported as a potential precipitating factor in some cases. Vaccinations, including bacillus Calmette-Guérin (BCG) and H1N1 influenza vaccines, have been associated with pustular psoriasis. Cases have also been documented in the setting of COVID-19 infection and following COVID-19 vaccination.[12][13] Psychological stress is frequently reported as a disease-exacerbating factor.

Epidemiology

Pustular psoriasis is a rare disease affecting both children and adults and demonstrates a bimodal age distribution. In adults, disease onset typically occurs between ages 40 and 50, whereas pediatric cases commonly present during infancy. Greater disease prevalence has been reported among Asian populations than among Caucasian populations.[14] Pustular variants account for approximately 1% of all clinical cases of psoriasis vulgaris.[15]

GPP is an uncommon condition with variable epidemiologic characteristics. In France, age- and sex-standardized cumulative prevalence and incidence rates have been reported at 45.2 and 7.1 cases per million, respectively.[16] In Japan, the estimated prevalence is 7.46 cases per million.[17] Pediatric GPP is uncommon but well-documented. The reported age at presentation ranges from 6 weeks to 10 years, including 1 documented case in a 6-week-old infant.[18]

Palmoplantar pustulosis and ACH have reported mean ages of onset of 43.7 and 51.8 years, respectively.[19] Annular pustular psoriasis in children has a mean age of onset of approximately 6 years.[20] Sex distribution in GPP varies geographically. In the US, the male-to-female ratio is approximately 1:1. Globally, female predominance has been reported, with female-to-male ratios of 1.5 for ACH, 1.7 for GPP, and 3.5 for palmoplantar pustulosis.[21][22] Common comorbidities include hypertension, ischemic heart disease, and hyperlipidemia.

Pathophysiology

The exact pathogenesis of pustular psoriasis remains incompletely understood. However, several mechanisms have been proposed based on cytokine expression patterns and therapeutic responses to targeted medications. A combination of genetic susceptibility and exposure to precipitating factors, such as withdrawal of systemic corticosteroids, may result in upregulation of specific cytokines and neutrophilic accumulation within the epidermis. Dermal dendritic cells also release elastase, which may contribute to pustule formation. Both pustular psoriasis and chronic plaque psoriasis demonstrate overexpression of IL-1, IL-17, IL-23, IL-36, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). However, IL-1 and IL-36 expression appears to be more prominent in pustular psoriasis. Proposed pathogenic mechanisms are discussed below.

Deleterious germline mutations in IL36RN have been identified in both familial and sporadic cases of GPP across diverse populations, including the UK, Germany, Tunisia, Malaysia, China, and Japan. Mutation patterns vary among populations, with evidence supporting a founder effect. In European populations, the most common mutation, IL36RN p.Ser113Leu, occurs in approximately 0.03% of healthy individuals. Patients with GPP harboring IL36RN mutations are more likely to develop early-onset disease and exhibit a pronounced systemic inflammatory response.[23][24]

IL36RN encodes the IL-36 receptor antagonist, which is primarily expressed in the skin and functions as an antagonist to 3 proinflammatory IL-1 family cytokines: IL-36α, IL-36β, and IL-36γ. These cytokines activate intracellular signaling cascades, including the NF-κB and MAPK pathways, and are modulated by cytokines released by Th17 cells and TNF-α. Although IL-36 cytokines are also overexpressed in plaque psoriasis, the mechanisms of IL-36 dysregulation in GPP appear to differ.

IL-36 receptors are constitutively expressed on dermal dendrocytes, CD4+ T cells, and macrophages. Receptor activation promotes maturation of monocyte-derived dendritic cells and release of cytokines, including IL-1, IL-6, IL-23, TNF-α, and IFN-γ. These cytokines contribute to neutrophil recruitment and cutaneous inflammation. Studies have also identified IL-36 receptor antagonist deficiency in patients with pustular psoriasis. Successful treatment with a novel monoclonal antibody targeting the IL-36 receptor has been reported in affected patients.[25]

Mutations in CARD14 have been occasionally reported, particularly in individuals with coexistent plaque psoriasis. These mutations result in increased activation of NF-κB signaling and upregulation of IL-8 and IL-36γ expression. Mutations in AP1S3, more commonly observed in patients with GPP and ACH, lead to increased IL-36α expression and impaired innate immune responses through disruption of TLR3 signaling.

IL-6 signaling has gained attention for its role in the pathogenesis of pustular psoriasis. The IL-6 receptor exists in both membrane-bound and soluble forms, a feature that distinguishes it from other cytokine receptors, which are exclusively membrane-bound. The IL-6/IL-6 receptor complex, together with the ubiquitously expressed gp130 subunit, activates the JAK/STAT and RAS/MEK/ERK/MAPK signaling pathways, promoting downstream gene transcription. IL-6 exerts broad immunologic effects, including induction of acute-phase protein synthesis, maturation of B cells, differentiation of T cells, and promotion of Th17 cell development. IL-6 also stimulates neutrophil maturation from myeloid precursors, upregulates ICAM-1 and other endothelial adhesion molecules to facilitate neutrophil migration, and enhances production of proinflammatory cytokines such as IL-23 and IL-17, reinforcing the Th17-driven inflammatory loop.[26]

The pathophysiology of ACH has been a subject of prolonged debate. Case studies describing the transition from ACH to GPP, together with reported associations with IL36RN, CARD14, and AP1S3 variants, support a shared disease spectrum. ACH and GPP may represent opposite ends of a single inflammatory continuum.[27]

Histopathology

Many histopathological features of pustular psoriasis overlap with those of psoriasis vulgaris, including parakeratosis, hyperkeratosis with thickening of the stratum spinosum, elongation of rete ridges, reduction of the stratum granulosum, and thinning of the suprapapillary epidermis. In addition to the classic histologic features of psoriasis vulgaris, a prominent neutrophilic infiltrate is present in the papillary dermis and epidermis. Neutrophilic accumulation leads to disruption of keratinocyte desmosomal junctions (spongiosis), basal keratinocyte herniation into the papillary dermis, and formation of superficial microabscesses. Neutrophilic infiltration of the epidermis is more pronounced in pustular psoriasis than in other variants of psoriasis vulgaris.

The histologic findings in GPP are dominated by dense neutrophilic infiltration, which underlies the bright erythema and formation of sterile pustules. The defining feature is the accumulation of neutrophils within the epidermis. The epidermis is typically acanthotic, with numerous neutrophils present between eosinophilic strands of keratinocytes. Large neutrophilic aggregates often localize within the stratum corneum and are typically surrounded by parakeratosis.

Hallmark features of active pustular psoriasis include spongiform pustules of Kogoj and microabscesses of Munro, which are characteristic histologic patterns also observed in plaque psoriasis (see Image. Histopathology of Pustular Psoriasis). Despite these findings, the National Psoriasis Foundation advises that a skin biopsy is not essential for the diagnosis of GPP, as histologic features may be nonspecific.

Histopathologic findings in acute generalized exanthematous pustulosis (AGEP) may closely resemble those of GPP. Accordingly, clinical history and clinical presentation are generally more reliable than histologic examination for differentiation between these entities.[28]

History and Physical

Pustular psoriasis presents as numerous discrete or confluent superficial yellowish pustules on an erythematous background. Full-body skin examination should be performed, including careful evaluation of mucous membranes and nails, to identify additional signs of psoriasis and exclude alternative causes of pustulosis.

Pustular psoriasis may develop in individuals with longstanding plaque psoriasis, often following exposure to corticosteroids or other environmental triggers. Alternatively, onset may occur de novo, frequently after an infection. In either scenario, the earliest symptom is often a burning sensation of the skin, followed by progression to dryness and tenderness. Abrupt onset of high fever and severe malaise commonly follow these prodromal symptoms, although these features are not universally present.

Preexisting psoriatic plaques may evolve into numerous small pustules. Erythema intensifies, and pustules may extend to previously unaffected areas, particularly the flexural and genital regions. Pustular psoriasis may present as either diffuse or localized disease.

Generalized Pustular Psoriasis

Cutaneous findings vary and may include discrete pustules, lakes of pus, circinate lesions, erythematous plaques covered with pustules, or generalized erythroderma. Pustules often emerge in crops, followed by desiccation and exfoliation. Nail involvement may include thickening and formation of subungual collections of pus. The oral and oropharyngeal mucosa may be affected, with findings such as hyperemia, geographic tongue, or fissured tongue. Associated arthralgia may be reported in some individuals. Disease course may resolve spontaneously within days to weeks, with reversion to baseline psoriasis in some cases or progression to erythroderma in others.[29]

GPP demonstrates clinical heterogeneity in age of onset, severity, and disease course. Several overlapping phenotypes have been recognized. A variable relationship exists between GPP and plaque psoriasis. Plaque psoriasis may precede or follow GPP episodes, while GPP may also present as the sole phenotype without a history of plaque involvement. Clinical subtypes of GPP are defined by distinct morphological patterns and differences in natural history. Recognition of these subtypes is essential for accurate diagnosis and appropriate management, which includes the following:

• Von Zumbusch variant: The most acute and fulminant form of GPP. Named after Leo von Zumbusch, who first described the condition in 1910 in 2 siblings following topical treatment, this variant presents with widespread erythema, sterile pustulation, fever, systemic malaise, and skin tenderness. Diagnosis is based on clinical findings, laboratory abnormalities such as leukocytosis and elevated inflammatory markers (ESR or CRP), and histopathologic evidence of spongiform pustules. Pustules typically resolve within days, followed by prominent scaling. Chronic plaques of psoriasis may clear after the acute episode. In the original case, 9 recurrences were documented over a 10-year period.
• Annular variant: Characterized by erythematous, scaly lesions with pustulation along the advancing margin. Lesions expand centrifugally over hours to days with simultaneous central clearing. Also referred to as “subacute GPP” or the “circinate variant,” this form generally follows a subacute or chronic course and produces fewer systemic symptoms. Higher frequency has been reported in the pediatric population.
• Exanthematic variant: Manifests as a sudden eruption of small pustules that resolve spontaneously within a few days. Commonly follows infection or may be drug-induced, with lithium identified as a frequent trigger. Systemic symptoms are usually absent. Clinical and histologic overlap with pustular drug eruptions, particularly AGEP, complicates differentiation.
• Localized variant: Involves pustule formation within or at the periphery of existing psoriatic plaques. Often observed during unstable phases of chronic plaque psoriasis or after application of irritants, such as coal tar or anthralin.
• Impetigo herpetiformis variant: Refers to GPP occurring during pregnancy. The onset most commonly occurs in the 3rd trimester, although cases have been reported as early as the 1st month of gestation or  the immediate postpartum period. Eruptions typically begin on flexural surfaces as symmetrical, confluent pustules on inflamed skin, often originating in the groin. Lesions spread centrifugally, coalesce into plaques, and may leave reddish-brown pigmentation during healing. Mucosal involvement, including the tongue, oral cavity, and esophagus, may occur and may be erosive. Disease frequently persists until delivery and may continue into the postpartum period.[30]

GPP begins in the 1st year of life in approximately 30% of cases. The onset may occur during the first few weeks, though, in some instances, the disease is present at birth. Systemic symptoms are frequently absent in infancy, and mild cases may not require treatment. Lesions are often localized to flexural areas, such as the neck, and may persist in this distribution for extended periods. More severe presentations with systemic involvement require active intervention. Disease onset in children most commonly occurs between the ages of 2 and 10 years. While the von Zumbusch pattern may be observed, annular and circinate variants are more frequently encountered. Episodes may resolve within days. However, recurrent inflammatory relapses are common. In older children, clinical features resemble the adult form, and any of the established morphological patterns may be present.

Pustulosis of the Palms and Soles

Pustulosis of the palms and soles (palmoplantar pustulosis) is characterized by sterile pustules on the palmoplantar surfaces, often admixed with yellow–brown macules (see Image. Pustulosis on the Soles). Scaly erythematous plaques may also be present. A minority of patients demonstrate chronic plaque psoriasis at other body sites.

The condition follows a chronic course, with pustules restricted to the palmoplantar surfaces, in contrast to the natural history of GPP. Smoking may exacerbate disease activity, while stress and focal infections have been identified as triggering factors.

Pustulosis of the palms and soles is frequently associated with sterile inflammatory bone lesions in the context of SAPHO syndrome, characterized by synovitis, acne, pustulosis, hyperostosis, and osteitis. The condition may also present as a paradoxical reaction in patients receiving TNF inhibitors for conditions such as rheumatoid arthritis or inflammatory bowel disease.

Acrodermatitis Continua of Hallopeau

ACH is an uncommon presentation of psoriasis. Pustules are clinically observed on the distal segments of the fingers and, less frequently, the toes. Pustulation is frequently followed by scaling and crust formation. Pustules may also develop in the nail bed beneath the nail plate, with possible exfoliation of the nail plates. Transition to other psoriasis variants may occur. ACH may be associated with annulus migrans of the tongue.

Evaluation

Patients with suspected pustular psoriasis require careful evaluation, as the von Zumbusch subtype may be life-threatening. Laboratory investigations should include a complete blood count, which may demonstrate initial absolute lymphopenia followed by marked polymorphonuclear leukocytosis, potentially reaching 40,000/µL. An electrolyte panel should be obtained to assess for hypocalcemia, and a liver panel should be performed to evaluate transaminase levels. A pregnancy test should be ordered for all women of childbearing age.

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are often elevated, reflecting systemic inflammation. Hypoalbuminemia, hypocalcemia, and reduced plasma zinc levels are frequently observed, along with lipid profile abnormalities. A punch biopsy may be performed in equivocal cases.

Bacterial cultures of pustular fluid are typically negative unless secondary infection is present. Viral cultures and Tzanck smears are also negative. However, disruption of the epidermal barrier may predispose to bacteremia. Urinalysis may demonstrate albuminuria and urinary casts.

Treatment / Management

The first step in managing pustular psoriasis is identifying triggers, such as an infection. Subsequent management is directed toward urgent control of inflammation and stabilization of the disease course.

GPP, particularly the von Zumbusch subtype, may require hospital admission to ensure adequate hydration, bed rest, and prevention of excessive heat loss. Supportive care includes the use of bland topical compresses and saline or oatmeal baths, which help relieve discomfort and promote debridement of affected skin. Systemic symptoms, including fever and arthralgia, require treatment with antipyretics and anti-inflammatory medications.

Disease-specific systemic therapies, using agents such as acitretin, methotrexate, cyclosporine, and infliximab, are considered 1st-line treatment in adult patients. In pediatric patients, acitretin, cyclosporine, methotrexate, and etanercept are preferred.

Second-line therapies for GPP include the administration of biologic agents such as etanercept, adalimumab, ustekinumab, and secukinumab, as well as topical drugs, particularly corticosteroids, calcipotriene, and tacrolimus, for localized involvement of the palms and soles.[31] A small case series reported clinical improvement with bimekizumab in patients with palmoplantar pustulosis and palmoplantar plaque psoriasis presenting with pustules.[32] Treatment guidelines for 2nd-line therapies remain limited. Anecdotal reports describe paradoxical induction of pustular psoriasis with certain biologic agents, highlighting the need for further evaluation and consensus.[33](B3)

Data on the treatment of pustular psoriasis during pregnancy remain exceedingly scarce. Most commonly used regimens include the administration of systemic corticosteroids, cyclosporine, narrow-band UVB phototherapy, adjuvant antibiotic therapy, and topical agents. Certolizumab therapy is an option, given the agent's favorable safety profile for both mother and fetus.[34][35](B3)

Treatment modalities for ACH, a particularly refractory subtype, are primarily derived from case reports. The limited efficacy of topical agents, including corticosteroids, calcipotriol, tacrolimus, and fluorouracil, often necessitates alternative approaches. Systemic options include cyclosporine, systemic corticosteroids, retinoids, methotrexate, psoralen plus UVA (PUVA), UVB phototherapy, and biologic agents (including anti–TNF agents, IL-17 inhibitors, IL-12/IL-23 inhibitors, and anakinra), as well as apremilast and baricitinib. A proposed treatment algorithm recommends acitretin or methotrexate as initial therapy, followed by biologics such as adalimumab and secukinumab, with possible escalation to guselkumab. Cyclosporine may be utilized for short-term disease control.[36][37][38](B2)

Spesolimab is a selective, humanized monoclonal antibody targeting the IL-36 receptor. The agent was recently approved in both Europe and the US for the treatment of GPP flares in adults. Phase II randomized controlled trials demonstrated rapid and effective cutaneous clearance during acute flares and superiority to placebo in reducing flare frequency over 48 weeks of maintenance therapy. Safety and tolerability profiles were favorable.[39] In March 2024, the US Food and Drug Administration (FDA) granted an expanded indication for spesolimab to include adults and pediatric patients aged 12 years or older weighing at least 40 kg. (Source: FDA. Spesolimab Injection Prescribing Information. 2024) This decision was based on results from the 48-week Effisayil 2 clinical trial, which enrolled 123 participants. Treatment with spesolimab resulted in an 84% reduction in GPP flares compared with placebo.[40](A1)

Recent reports indicate successful use of IL-1 receptor antagonists, such as anakinra, in the treatment of pustular psoriasis. Tocilizumab, an IL-6 receptor inhibitor, has demonstrated efficacy in select cases of biologic-induced plantar pustular psoriasis.[41] This monoclonal antibody targets both membrane-bound and soluble IL-6 receptor complexes, thereby inhibiting IL-6–dependent STAT1 and STAT3 signaling pathways. Notably, tocilizumab has also been associated with paradoxical development of psoriasiform dermatitis in patients treated for rheumatoid arthritis.[42](B2)

Imsidolimab is a humanized, affinity-matured immunoglobulin G4 monoclonal antibody that antagonizes IL-36 signaling by binding to the IL-36 receptor. Two phase 3 trials were conducted at 26 clinical sites in 11 countries to evaluate the efficacy of imsidolimab in the treatment of GPP. A significantly higher proportion of patients with GPP receiving a single intravenous dose of imsidolimab achieved clear or almost clear skin at 4 weeks compared with placebo.[43]

Janus kinase (JAK) inhibitors demonstrate high response rates, rapid clinical improvement, and generally tolerable safety profiles. However, existing evidence remains limited by small sample sizes, short follow-up durations, and reliance on case-based data. JAK inhibitors are a potential therapeutic option and require further evaluation in larger controlled trials to establish long-term efficacy and safety.[44](A1)

Differential Diagnosis

Pustular psoriasis is a clinically heterogeneous condition with variable manifestations, making accurate diagnosis and differentiation from other pustular dermatoses challenging. The differential diagnosis includes disorders characterized by widespread nonfollicular pustules, discussed below.

AGEP presents as a febrile eruption characterized by erythema and widespread pustules. Histopathologic features include neutrophilic exocytosis, intraepidermal or subcorneal pustules, papillary dermal edema, and a dermal infiltrate composed of neutrophils and eosinophils. AGEP is most often triggered by medications or infections and typically resolves within 2 weeks following removal of the inciting factor.

Although AGEP shares clinical features with GPP, including sudden onset of pustules, fever, and leukocytosis, differentiation may be supported by the presence of numerous discrete, short-lived pustules, a recent history of drug exposure, and rapid resolution after drug cessation. Consensus among experts (90%) supports that the presence of eosinophils, particularly within microabscesses, favors a diagnosis of drug-induced pustulosis.[45] AGEP has been associated with IL36RN mutations, similar to those identified in GPP, pustulosis of the palms and soles, and ACH. These genetic and clinical overlaps have led to consideration of AGEP as a drug-induced variant within the pustular psoriasis spectrum.[46]

Subcorneal pustular dermatosis, or Sneddon–Wilkinson disease, is characterized by erythematous pustules, often involving the trunk and intertriginous areas. The association between this condition and pustular psoriasis remains controversial. Subcorneal pustular dermatosis is typically benign, relapsing, and not associated with systemic symptoms. A diagnostic clue is the presence of hypopyon pustules, containing clear fluid in the upper portion and purulent yellow material in the lower portion.[47]

Immunoglobulin A pemphigus may also mimic GPP. However, histopathologic features and characteristic immunofluorescence patterns allow differentiation.

Necrolytic migratory erythema associated with glucagonoma may resemble pustular psoriasis. Associated features, including weight loss, glossitis, and anemia, assist in differentiation.

During the acute phase of GPP, fever, leukocytosis, and elevated inflammatory markers may mimic systemic infection. This clinical overlap may lead to inappropriate discontinuation of immunosuppressive therapy, with potential exacerbation of underlying disease.

Prognosis

Pustular psoriasis is a chronic disease characterized by recurrent episodes or flares. Treatment is directed at shortening the duration of relapses, preventing complications, and prolonging disease-free intervals. Compared with other subtypes, the von Zumbusch variant carries a higher risk of mortality due to systemic involvement, particularly in the presence of comorbidities such as cancer, renal failure, or liver failure. Localized subtypes of pustular psoriasis are associated with a substantially lower mortality risk. Subacute annular and circinate forms are generally associated with a favorable prognosis, particularly in pediatric patients. Outcomes are likewise better when a clear precipitating factor is identified, as in pustular psoriasis of pregnancy. In contrast, pustular psoriasis evolving from ACH appears to carry the poorest prognosis.[48][49]

Complications

Reported mortality rates for GPP range from 4% to 24%, underscoring the potential severity of the condition.[50] Patients are often systemically unwell and may develop life-threatening complications, including the following:

• Renal compromise may arise due to hypovolemia and oligemia, potentially resulting in acute kidney injury.
• Profound hypoalbuminemia is common, resulting from both rapid loss of plasma proteins into tissues and impaired intestinal absorption.
• Secondary hypocalcemia may develop as a consequence of low albumin levels.
• Abnormalities in liver function tests are frequently observed, and in some cases, cholestatic jaundice may occur due to neutrophilic cholangitis.[51]
• Although rare, acute respiratory distress syndrome has been reported.
• Superimposed Staphylococcus aureus infection may complicate the disease course.
• Telogen effluvium, a form of diffuse hair shedding, may occur 2 to 3 months after the acute illness.
• Amyloidosis is a rare late complication associated with chronic inflammation.

In the setting of impetigo herpetiformis, additional complications may include delirium, gastrointestinal disturbances, tetany, cardiac or renal failure, and death in severe cases. The risk of placental insufficiency is elevated, with increased likelihood of stillbirth, neonatal death, or congenital anomalies. These obstetric complications are directly related to disease severity and chronicity. Recurrence is common in subsequent pregnancies and may also occur with the use of oral contraceptives.