Answer: A

Generalized pustular psoriasis (GPP) is a severe form of psoriasis characterized by diffuse pustules and plaques with erythema of the underlying skin. The course of the disease varies, with waxing and waning symptoms potentially occurring for a number of years.1 GPP is a rare subtype of psoriasis that can be found in all racial and ethnic groups and in both sexes. Patients may or may not report a prior diagnosis of plaque psoriasis. The disease can occur at any age but is most prevalent between the ages of 40 and 59 years. Common associations include inflammatory polyarthritis, diabetes, hypertension, and dyslipidemia.2,3

Based on appearance and history, GPP is classified into the following subtypes: von Zumbusch, impetigo herpetiformis, and infantile and juvenile GPP.3-5 GPP of von Zumbusch occurs acutely and is accompanied by malaise, fever, leukocytosis, and an elevated ESR.1,4,5 The pustules are typically 2 to 3 mm in size and occur at the periphery of an erythematous base. Extracutaneous involvement can include acute renal failure, interstitial pneumonitis, cholestasis, and cholangitis. These manifestations may warrant inpatient monitoring.5

Impetigo herpetiformis, also known as GPP of pregnancy, may present late in pregnancy, with the lesions resolving in the postpartum period. Lesions typically begin in axillary, groin, submammary, popliteal, and antecubital areas symmetrically. The lesions then spread radially and typically spare the palms, soles, and face.Cases may be severe, with symptoms and signs including malaise, fever, nausea, leukocytosis, and an increased ESR. Hypocalcemia resulting in tetany has also been observed.4,5

Infantile and juvenile GPP is similar to adult-onset GPP but typically has a more benign course and more frequently resolves spontaneously.3 These cases are exceptionally rare.5

Although the etiology of GPP is unknown, potential triggers of disease include drugs, infections, psychological stress, pregnancy, and hypocalcemia.2 Both bacterial and viral infections have been cited as potential inciting factors for GPP.  In particular, GPP may occur alongside an upper respiratory tract infection due to the activation of neutrophils.4 Conditions resulting in fluctuating hormone levels, such as stressful life events and pregnancy, are associated with the development of GPP.2,3 Systemic corticosteroid withdrawal in patients with plaque psoriasis may also incite GPP.2,3

Other drugs that have been implicated in the disease include antihypertensive agents, antibiotics, bupropion, terbinafine, and various biologic agents.3 A pustular reaction to a new drug, however, warrants consideration of acute generalized exanthematous pustulosis (AGEP).

Histologic examination of GPP reveals epidermal spongiform pustules of Kogoj, neutrophilic infiltrate, dilated tortuous vessels, Munro microabscesses, parakeratosis, epidermal edema, and epidermal hyperplasia.4,5

Previously, GPP was considered a subtype of plaque psoriasis; however, recent research has identified unique genetic factors distinct to GPP.5 Mutations in the IL36RN gene, which codes for interleukin-36 receptor antagonist (IL-36RA) protein, result in increased proinflammatory pathways including overproduction of IL-36 and IL-1 cytokines. GPP with this genetic mutation is called “deficiency in IL-36RA” or “DITRA”.4,5 Notably, not all patients presenting with GPP have with this genetic variant.4

Treatment of GPP depends on a number of factors. Recurrences are common, so long-term therapy is recommended. In adults with GPP, treatment with a retinoid such as acitretin is most efficacious for nonacute flares. Retinoids are associated with capillary leak syndrome, and they are contraindicated in pregnant women due to teratogenic effects.4-6 Other first-line treatments include infliximab, methotrexate, and cyclosporine.

In patients with severe acute disease, cyclosporine and infliximab are first-line agents due to their rapid onset.4 First-line therapies for pregnant patients include oral corticosteroids, cyclosporine, and infliximab. First-line therapies for juvenile and infantile pustular psoriasis include acitretin, cyclosporine, methotrexate, and etanercept. However, acitretin has been linked to various skeletal toxicities, so this association should be considered when treating children.4,5 Second-line therapies for all subtypes include topical corticosteroids, phototherapy (psoralen plus ultraviolet A), adalimumab, and etanercept. 4-6

The presentation of GPP varies from fairly benign to extremely severe. Patients with severe GPP and comorbid conditions may be unable to tolerate first-line treatments. In a case report by Jeon and Nakamura, treatment with a phosphodiesterase type 4 (PDE-4) inhibitor was found to be effective for a patient with GPP, hepatitis C virus infection, liver cirrhosis, and hepatocellular carcinoma, as cyclosporine and infliximab are contraindicated in patients with liver disease.7 In the case described, GPP was found to be markedly reduced at 3 weeks and absent at 6 weeks.7 PDE-4 inhibitors decrease tumor necrosis factor and interleukin levels, which counteracts the dysregulation of IL-36 and IL-1 cytokines in patients with DITRA.7

Other therapies targeting immunologic pathways, such as ustekinumab (a monoclonal antibody against IL-12 and IL-23), show promise for the management of GPP.4 In the future, biologic therapies may replace or further supplement traditional systemic therapies as first-line treatments of GPP. Due to the rarity of GPP, the current literature lacks high-quality randomized controlled trials; therefore, these recommendations are based on case reports and clinical experience.6,8

The differential diagnosis of GPP includes AGEP, palmoplantar pustular psoriasis, pustular erythema multiforme, annular pustular psoriasis, and dermatitis with secondary infection. Differentiating GPP from AGEP is particularly important when making the diagnosis. AGEP is associated with antibiotic use and tends to improve more quickly than GPP.5 Diagnostic criteria of GPP include:

  • Multiple pustules on erythematous skin;
  • Constitutional symptoms;
  • Spongiform pustules on histologic examination; and
  • Laboratory abnormalities such as elevated ESR, elevated C-reactive protein, or leukocytosis.6

The patient in the case described earlier was prescribed oral cyclosporine resulting in resolution of GPP.

Click to the next page for Case 2.