A fever and a pruritic rash on the torso

Case #1: Pustular psoriasisPustular psoriasis is a subtype of psoriasis that is traditionally classified into generalized and localized forms. The two major clinical variants of generalized pustular psoriasis (GPP) are von Zumbusch psoriasis (acute GPP) and annular pustular psoriasis (subacute...

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Case #1: Pustular psoriasis

Pustular psoriasis is a subtype of psoriasis that is traditionally classified into generalized and localized forms. The two major clinical variants of generalized pustular psoriasis (GPP) are von Zumbusch psoriasis (acute GPP) and annular pustular psoriasis (subacute GPP). Acute GPP presents with widespread pustulation, erythema, and systemic symptoms, whereas annular pustular psoriasis exhibits annular or figurate erythematous plaques with peripheral pustules.^1,2 Acute GPP occurring in pregnancy is known as impetigo herpetiformis.^3,4 The major localized forms of pustular psoriasis include palmoplantar pustulosis, a chronic pustular condition confined to the palms and soles, and acrodermatitis continua of Hallopeau (ACH), a pustular eruption of the digits.^1,2

The exact prevalence of pustular psoriasis is not known, and there does not appear to be a strong predilection for sex or race.^5,6 Incidence is higher in middle-aged adults, most commonly in those between the ages of 40 and 60 years.⁵ Annular pustular psoriasis is the most common form of pustular psoriasis in children.^1,4

The pathophysiology is not well described, but the clinical features are thought to be attributed to enhanced polymorphonuclear leukocyte chemotaxis.⁷ Mutations in IL36RN, the gene encoding the interleukin-36 receptor antagonist, lead to unregulated proinflammatory pathways that are believed to be the cause of the neutrophil activation and migration associated with pustular psoriasis.^8,9

Predisposing factors of GPP include the withdrawal of systemic steroids, cyclosporine, potent topical corticosteroids, and ustekinumab, as well as upper respiratory tract infections and hormonal changes during pregnancy.^1,2 In localized GPP, infection or trauma of a digit has been shown to precede ACH, and smoking is associated with the palmoplantar form of pustular psoriasis.^10,11 Additional reported risk factors include sunlight exposure, hypocalcemia, terbinafine, acetazolamide, and salicylates.²

Acute GPP is the most severe form of the disease and is characterized by painful, widespread, patchy erythema studded with pustules.¹ Onset is abrupt and recurrent, and pustules frequently converge to form larger areas of pustular accumulations, known as lakes of pus, that resolve after several days, leaving scaling and erythema.^1,2 Pruritus, intense burning, and mucous membrane lesions resulting in cheilitis and geographic tongue are common.^1,2 Manifestations of systemic illness, including fever, arthralgia, hypocalcemia, jaundice, erythroderma, cachexia, pneumonia, hepatitis, and congestive heart failure, often accompany these symptoms.^1,2,5 Acute GPP can be fatal if left untreated.^2,5

Annular pustular psoriasis (subacute GPP) presents as annular erythematous plaques expanding centrifugally for a period of hours to days, with peripheral pustular formation and central healing.^1,4 As with acute GPP, residual scale remains after pustular resolution.

Localized forms of pustular psoriasis are rare.¹² ACH presents with pustules studding erythematous plaques that are usually limited to the distal areas of one or two digits, often of the fingers but sometimes the toes.^2,11 It is a chronic inflammatory disease that often involves pustular formation inside the nail bed, leading to shedding of nail plates, onychodystrophy, and anonychia.^1,11 Transition to GPP can occur, but is uncommon.¹

Palmoplantar pustulosis is characterized by clusters of sterile pustules mixed with yellow-brown macules and scaly erythematous plaques localized to the palms and soles. Pruritus, burning pain, and inflammatory bone lesions are often associated.¹

Histologically, pustular psoriasis resembles psoriasis vulgaris, exhibiting parakeratosis, elongated rete ridges, neutrophil migration into the epidermis, and mononuclear perivascular infiltrate in the upper dermis.^12,13 Spongiform pustules of Kogoj, formed by the aggregation of neutrophils between keratinocytes, are a characteristic histologic feature.^13,14

The diagnosis of pustular psoriasis is made using the history, physical examination, histopathology, and laboratory test results. A history of psoriasis, withdrawal or introduction of drugs (especially systemic steroids), and systemic symptoms such as fever and cachexia, suggest acute GPP.^1,6 In patients suspected of having GPP, a skin biopsy is usually obtained due to its ability to distinguish between GPP and other pustular eruptions. Serologic test results revealing leukocytosis, lymphopenia, elevated erythrocyte sedimentation rate, hypocalcemia, decreased albumin, and elevated liver enzymes further aid in the diagnosis of acute GPP.^1,5

The differential diagnosis of pustular psoriasis includes acute generalized exanthematous pustulosis (AGEP), immunoglobulin A (IgA) pemphigus, secondarily infected dermatitis, and tinea corporis.

AGEP presents with fever and multiple nonfollicular pustules on an erythematous background. It can be very difficult to distinguish from acute GPP, particularly in AGEP patients who also have the IL36RN mutation.¹⁴ Rapid resolution within 2 weeks of drug discontinuation, no personal or family history of psoriasis, and the presence of eosinophils and necrotic keratinocytes favors a diagnosis of AGEP. Acanthosis, papillomatosis, and spongiform pustules of Kogoj point to acute GPP.^14,15

The annular pustular eruptions of IgA pemphigus, a rare autoimmune disorder, may be confused with the annular form of pustular psoriasis. However, IgA pemphigus primarily affects middle-aged or elderly adults, whereas annular pustular psoriasis is most common in childhood.^4,13 Additionally, IgA deposits in the epidermis revealed by direct immunofluorescence differentiate this disorder from annular pustular psoriasis.¹³

Clinical presentation of tinea corporis resembles that of annular pustular psoriasis, consisting of annular, erythematous, scaling lesions and central clearing.^16,17 A positive potassium hydroxide examination result indicates the former.

Treatment of pustular psoriasis is aimed at minimizing skin manifestations, controlling systemic illness, and alleviating symptoms. In cases of relatively stable GPP, acitretin is the treatment of choice, with methotrexate as an alternative.^2,18 Cyclosporine and infliximab are used for patients with severe acute GPP.¹⁸ In patients who are not responding to these first-line therapies, biologic agents such as etanercept and adalimumab can be used.¹⁸ Potent topical corticosteroids such as clobetasol and halobetasol are first-line treatments for ACH and palmoplantar pustulosis.^19,20 Moisturizers, oatmeal baths, and wet wraps may provide symptomatic relief.

The patient in this vignette was diagnosed with acute GPP and admitted to the hospital for severe acute GPP with systemic symptoms. The patient was then started on cyclosporine for stabilization. The patient was slowly weaned off cyclosporine and started on acitretin for maintenance therapy. 

Case #2: Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) is a rare, adverse cutaneous reaction, most often caused by drugs or infection.¹⁵

The prevalence of AGEP is 1 to 5 cases per million per year.^2,21 It can occur at any age, although most patients are adults. Men and women are equally affected.¹⁵

Drugs are the causative factor in 90% of AGEP cases^22,23; the most frequent triggers are antibacterial agents, particularly aminopenicillins and macrolides, antimalarials, antimycotics, calcium channel blockers, carbamazepine, and paracetamol.^2,15,24 Viral causes are more common in children with AGEP, and spider bites have also been implicated.²³

Research into the pathophysiologic mechanism of AGEP suggests a pattern of immune dysregulation caused by drug-specific T cells resulting in neutrophil activation, migration, and accumulation in the epidermis.^25,26 Additionally, IL36RN mutations, found in acute GPP, have also been discovered in a few cases of AGEP, suggesting that the two may share a common genetic basis.^13,27

The histologic picture of AGEP shows a subcorneal or superficial intraepidermal pustule, usually with edema of the papillary dermis, necrotic keratinocytes, eosinophils in the pustules or dermis, and perivascular infiltrates with neutrophils.^15,26

AGEP usually begins with an abrupt, pruritic or burning edematous erythema occurring in the intertriginous areas or the face.^2,15 Multiple pinhead sized, nonfollicular sterile pustules (each less than 5 mm in diameter) then appear on top of the erythema, most often in the skin folds.^15,28 The pustular eruption occurs within a few days (usually <5) and rapidly becomes widespread, extending to the trunk and limbs.^2,23 Confluence of the pustules may occur, as can other skin findings including facial edema, nonspecific purpuric lesions, a positive Nikolsky sign, and blisters.² Mucous membrane involvement, if any, is usually limited to the lips.^2,15

Patients with AGEP often present with fever, leukocytosis with a neutrophil count >7 × 10⁹/L, and mild eosinophilia.¹⁵ Skin symptoms usually resolve spontaneously within 4 to 10 days, leaving a characteristic postpustular pinpoint desquamation.^15,23

The diagnosis of AGEP can be made based on the morphologic picture, histopathology, and clinical course.^2,15,21 Gram staining and culture is helpful to rule out bacterial infection, and patch testing with the suspected agent is useful for identifying the cause of the condition.²

The differential diagnosis of AGEP includes acute GPP (von Zumbusch), bullous impetigo, drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome/toxic epidermal necrolysis, and subcorneal pustular dermatosis (Sneddon-Wilkinson disease).

Acute GPP is characterized by recurrent, abrupt onset of pustules, erythema, and systemic symptoms and can be very difficult to distinguish from AGEP.^14,15 Histologically, acanthosis, papillomatosis, and spongiform pustules of Kogoj suggest acute GPP, whereas necrotic keratinocytes, dermal edema, and eosinophilia indicate AGEP.^2,14,15 Other clues that favor the diagnosis of acute GPP include a history of psoriasis, absence of drug exposure, longer duration of fever and pustular eruption, and psoriatic arthritis.¹⁵

Sometimes patients with DRESS can present with pustules, producing lesions that look similar to those of AGEP. However, DRESS often has a less pronounced pustular component, multiple systemic symptoms including fever, lymphadenopathy, hepatitis, and nephritis, and is characterized by a longer drug latency period—over 2 weeks.^15,29

Subcorneal pustular dermatosis presents with pustules in the trunk and intertriginous areas that are usually larger than those in AGEP, and are flaccid. Onset is less acute, and the eruptions are chronic and relapsing.^15,30

Treatment for AGEP involves discontinuation of the offending drug and symptomatic treatment. Moist dressings, topical corticosteroids, and antihistamines can be used to relieve pruritus, and the application of emollients is helpful during the desquamation phase.² Because AGEP is a self-limiting condition with an excellent prognosis, use of systemic corticosteroids is discouraged.^15,21

The patient in this vignette was diagnosed with AGEP; the likely causative agent was erythromycin. Due to the severity of systemic symptoms, the patient was admitted to the hospital for observation and symptomatic treatment. The patient’s rash and symptoms significantly improved within a week. The patient was advised to avoid self-medicating and macrolide antibiotics in the future.

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Warren Chan, BS, MS, is a medical student, Connie Wang, MD, is a dermatology resident, and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine in Houston.

References

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