Scaly plaques are characteristic of psoriasis vulgaris; in PP, patients develop multiple pustules on psoriatic lesions. They usually develop within hours after the onset of erythema, and in the majority of cases, such a bout of PP cannot be ascribed to any known trigger. Pustules initially measure only few millimeters in diameter, but they may coalesce and form lakes of pus. Eventually, they may break, drain their content and dry. If crusts form, they are typically very thin and shed easily. New pustules preferentially occur at the borders of expanding plaques. Erythema persists during the whole process, and the affected skin is generally tender. Predilection sites are the trunk and limbs; localized PP is designated palmoplantar PP if restricted to hands and feet [9]. Mucous membrane involvement has occasionally been reported, and patients may show geographic tongue or fissured tongue).

Generalized PP differs from the localized form of the disease in that affected individuals also develop systemic symptoms, commonly consisting in malaise, fever, chills, myalgia and arthralgia. Flare-ups of generalized PP may last one or two weeks, and as soon as dermatological symptoms subside, the patient's general condition will also improve. In contrast, localized PP often follows a chronic course.

It is not uncommon to observe symptoms associated with psoriasis vulgaris before, during or after an episode of PP.

Diagnostic criteria have been established as follows [10]:

• Multiple aseptic pustules on erythematous skin
• Histopathological confirmation of Kogoj's spongiform pustules
• Hematological alterations consistent with PP, e.g., leukocytosis with left shift; increase of erythrocyte sedimentation rate, C-reactive protein, immunoglobulins; hypoproteinemia; hypocalcemia

For generalized PP, this list is expanded by adding the presence of systemic symptoms as described in the previous paragraph.

Accordingly, culture of a pustule's content, histopathological analysis of a tissue specimen, and laboratory analysis of a blood sample is required in order to confirm a tentative diagnosis of PP. In a patient with a medical history of PP, a less extensive workup is often sufficient. In fact, Umezawa and colleagues propose that any listed criterion may be replaced by the recurrence of clinical or histopathological findings indicative of PP [10].

In case of generalized PP, it is important to monitor hemodynamics and organ function. Quantitative and qualitative analysis of urine production is generally required to that end.

Treatment aims at relieving dermatological and systemic symptoms. The following recommendations have recently been given by the US-American National Psoriasis Foundation [3]:

• Localized PP
• Topical corticosteroids or calcipotriene and topical or oral PUVA are usually sufficient to control this form of the disease.
• Otherwise, tacrolimus may be applied topically. Phototherapy has also been recommended as a second-line therapy.
• If systemic therapy is preferred, acitretin, cyclosporine, PUVA and PUVA with etretinate may be helpful.
• Second-line systemic treatment consists in the application of adalimumab, alefacept, etanercept, or infliximab.
• Childhood generalized PP
• Acitretin (possibly combined with oral prednisone), methotrexate, cyclosporine and etanercept are listed as first-line treatments.
• To date, TNF-α antagonists adalimumab, infliximab are considered second-line options.
• UVB phototherapy is indicated after control of acute symptoms with any of the aforementioned therapies.
• Adult generalized PP
• Acitretin is the drug of choice, with cyclosporine, methotrexate, and infliximab being valuable alternatives as first-line therapeutics.
• Adalimumab, etanercept, and topical application of corticosteroids, calcipotriene or tacrolimus, in case of limited extension and possibly combined with PUVA, may be considered in case of an insufficient response to therapy.

Additionally, patients suffering from generalized PP usually require hospitalization and fluid therapy. It may be necessary to correct abnormal electrolyte concentrations and to compensate for protein loss.

Generalized PP is commonly associated with systemic complications that may be life-threatening. According to the retrospective analysis of cases registered in France, this form of the disease was associated with 2% mortality [7]. Life-threatening complications are sepsis, heart failure, renal tubular necrosis due to oligemia, and liver failure. They generally coincide with extensive erythroderma. It has been suggested that the patient's prognosis worsens with age, but the aforecited study has not confirmed this hypothesis. In contrast, disease severity and deviation from treatment recommendations have been identified as unfavorable prognostic factors. Even though momentary remission is achieved, the likelihood of recurrence is high.

Localized PP may also follow a course of apparent remission and recurrence, but more commonly manifests as a chronic disease that interferes with life quality for years. Mortality due to localized PP has not been registered, but may possibly result from secondary infections and subsequent sepsis.

Both genetic and environmental factors play critical roles in PP pathogenesis.

With regards to the former, sequence anomalies affecting genes encoding for interleukin-36 receptor antagonist (IL36RN) and caspase recruitment domain family, member 14 (CARD14) have been related to the disease [4]. IL36RN is primarily expressed in the skin; it is a competitive antagonist of the interleukin-36 receptor and thus inhibits the activation of downstream pro-inflammatory cascades. Accordingly, dysfunction of IL36RN is accompanied by sustained inflammation. On the other hand, gain-of-function mutations of CARD14 lead to enhanced activation of NF-κB signaling pathways and release of pro-inflammatory cytokines and chemokines. Interestingly, there seem to be genotypic differences between PP patients who present with psoriasis vulgaris and those that don't: IL36RN mutations are assumed to be more prevalent in sole PP while patients suffering from combined forms of psoriasis are more likely to carry CARD14 mutations.

PP may follow a recurrent course and this observation led to the hypothesis of environmental factors triggering acute episodes of the disease. In this context, drug-induced PP has most frequently been described. In detail, the following compounds have been suspected to trigger PP [5]:

• Non-steroidal anti-inflammatory drugs, e.g., dilclofenac, indomethacin, oxyphenbutazone, phenylbutazone
• Antimalarials, e.g., hydroxychloroquine, chloroquine
• β-adrenergic antagonists, e.g., atenolol, propranolol
• Antibiotics, e.g., penicillin, sulphonamides
• Psychotherapeutic drugs, e.g., nitrazepam, trazodone
• Amiodarone
• Lithium
• Mestranol
• Morphine

However, distinction between drug-induced PP and pustular drug eruptions is not an easy task. Recurrence of psoriatic lesions after cessation of drug therapy is indicative of the former, though .

Furthermore, infectious diseases, physical and chemical noxious agents as well as pregnancy have been proposed to induce episodes of PP. In most cases, there is only circumstantial evidence supporting those theories and to date, many cases are still deemed idiopathic.

While psoriasis vulgaris is a common disorder, PP is much less prevalent. This particularly applies to pediatric patients and according to a retrospective study conducted in Serbia, PP accounted for 1% of psoriasis cases in individuals aged less than 16 years [6]. The mean age at symptom onset has repeatedly been stated to be 50 years. Precise epidemiological data are available for generalized PP only, with reported annual incidence rates of less than 1 per 1,000,000 inhabitants in France and Japan [4] [7]. Prevalence of generalized PP has been estimated to less than 2 per 1,000,000 people. The respective studies have also shown a slight female predominance among individuals suffering from generalized PP.

The histopathological equivalent of PP-related pustules are spongiform pustules of Kogoj [4]. It is characterized by epidermal necrosis and marked exocytosis of neutrophils. The designation "spongiform" refers to the fact that degenerated keratinocytes persist and give the epidermis its sponge-like appearance. Further common findings are epidermal hyperplasia and parakeratosis, elongation of rete ridges, and dermal vasodilation.

The direct trigger of pustule formation is the activation of neutrophil granulocytes, which, in turn, may be caused by any of those environmental factors mentioned above. Additionally, an exacerbated activation of neutrophils may be the result of a sudden cessation of anti-inflammatory therapy. Thus, PP patients may report to have recently discontinued the use of corticosteroids. Infections may cause acute neutrophil activation; the precise link between drug-mediated effects or endocrinologic imbalances and the induction of an inflammatory response in the skin is not known. Based on current knowledge regarding pathogenic sequence anomalies, it may be assumed that malfunction of regulatory mechanisms accounts for the inflammation to become chronic.

Retinoids are highly effective in PP patients and affect T cells and keratinocytes [8]. This observation implies those cells to partake in PP pathogenesis. Presumably, they form part of a complex network of cell-cell-interaction and cytokine release that ultimately result in locally increased concentrations of IL-8, Gro-α, MIP-2, arachidonic acid metabolites and certain complement factors that attract neutrophils into the epidermis.

Genetic counseling is not usually offered to patients affected by PP since the influence of gene variants on PP pathogenesis is only poorly understood. If a patient is diagnosed with PP, they should be educated regarding possible triggers of recurrence; patients may also associate determined situations with flare-ups of their disease. Such situations should be avoided. No general recommendations can be given to that end because single environmental factors may have beneficial effects in some patients and be detrimental in others.

Pustular psoriasis (PP) is an uncommon form of psoriasis. It is typically diagnosed in adults and is characterized by pus-filled eruptions covering more or less large areas of erythematous, sometimes scaly skin. Distinct forms of PP have been described, and designations may be based on the expansion of cutaneous lesions (localized PP vs. generalized PP, with the latter also being referred to as von Zumbusch PP), their anatomical location (e.g., PP palmoplantaris), and their precise appearance (e.g., annular PP, exanthemic PP) [1]. Mixed patterns have been described.

Localized PP often follows a chronic course, while generalized PP is associated with severe, potentially life-threatening bouts of erythroderma [2]. The latter is associated with extensive inflammation, vasodilation, loss of fluids and electrolytes, and may lead to hemodynamic failure. Accordingly, therapy consists in topical and systemic treatment of dermatological symptoms and, in case of generalized PP, in prevention and remediation of systemic complications. Acitretin, cyclosporine, and methotrexate have recently been recommended as first-line treatments for childhood and adult generalized PP [3]. Localized PP is generally treated topically, and corticosteroids, calcipotriene or tacrolimus may be applied to this end.

Psoriaris is a very common skin disorder and it has been estimated that about 2% of the overall population are affected by this disease. What is commonly known as psoriasis is referred to as psoriasis vulgaris by professionals. Besides psoriasis vulgaris, there are less prevalent forms of the disease, e.g., pustular psoriasis (PP).

PP is characterized by multiple pus-filled bumps that develop on psoriatic plaques, but scales are less prominent than in psoriasis vulgaris. The underlying skin is severely reddened, a condition known as erythema and indicating an inflammatory reaction taking place in the skin. Patients may present with localized PP, i.e., pustules merely develop in determined areas of the body, or with generalized PP. Here, large areas of the skin are affected by erythema and pustules. This severe inflammatory response may have systemic complications. Vasodilation, loss of fluids, electrolytes and protein may cause hemodynamic or multi organ failure. For instance, kidney function may be severely impaired if urine can no longer be produced due to hypovolemia and reduced glomerular flow rates.

Several treatment options are available. Some compounds used to treat PP patients may also be applied in case of psoriasis vulgaris, e.g., acitretin, methotrexate, and cyclosporine. Patients suffering from generalized PP may require hospitalization and fluid therapy to remedy systemic complications. Symptoms usually subside within a few weeks, but recurrence is likely. In contrast, localized PP does usually not follow this course of remission and recurrence but is a chronic disorder that may persist for years.

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