2.1 Describing GPP
The clinical course of GPP is heterogeneous; it can be considered a relapsing disease with recurrent flares, or a persistent disease with intermittent flares [
3,
5]. Disease flares manifest as the sudden appearance of large areas of painful, non-infectious pustules, which may co-present with fever, chills, and loss of appetite [
6,
7]. Symptom severity may vary with each flare for a given individual, and flares may occur several times per year or with long dormant periods between each episode [
6,
8].
GPP has been subcategorized into four forms based on the onset of flares and the morphology of lesions [
9]. GPP (also called GPP of von Zumbusch) presents with rapid onset (7 days or fewer) of a generalized pustular flare and may be experienced by up to 90% of patients with GPP [
9,
10]; it is recognized as the most severe presentation of the disease [
11]. Annular GPP presents with a generalized pustular flare that develops between 7 days and 3 months, and is often associated with relatively mild symptoms [
2,
12]. Chronic acral GPP presents with the onset of a generalized pustular flare over more than 3 months, with lesions that begin with an acral distribution in the extremities and then gradually spread into a generalized pustular flare [
9]. The ‘mixed GPP’ category captures patients who have features that are associated with more than one subtype, with localized pustular psoriasis that develops into a generalized pustular flare over a range of onset periods [
9].
GPP can manifest with or without concomitant plaque psoriasis [
7]. It is important to recognize that GPP is a distinct clinical entity from plaque psoriasis and that a differential diagnosis is critical [
6,
11,
13]. A diagnosis of GPP should be considered in patients with sudden onset of erythema and pustulosis, and emergency care may be required in patients with fever or severe pain, or with signs of systemic inflammation that may lead to respiratory, cardiac, or renal failure [
2,
11]. GPP should be distinguished from the transient, primary pustule formation that may occur at the periphery of plaques in patients with psoriasis vulgaris [
2,
3]. See the article on Diagnosis of Generalized Pustular Psoriasis (
https://doi.org/10.1007/s40257-021-00652-1).
2.2 Common Disease Characteristics
Several characteristics of GPP have become apparent from published case reports. It has been suggested that there may be a female preponderance in GPP; however, the extent of this varies by geographical region and between ethnicities. A study in 102 patients from Malaysia reported a 2:1 ratio of GPP in females versus males; a study of 74 patients in the US reported a 1.03:1 ratio; and in a study of over 700 patients in Japan, 51.5% were female [
9,
10,
14]. Findings from a recent inpatient database of 1516 people with GPP in Japan reported that 56% were male, and a registry in Western Japan observed that 52% of 102 GPP cases were male [
15,
16]. GPP can present at any age, including as juvenile GPP [
8]; however, the majority of cases present in the fifth decade and the mean age at diagnosis has been reported as 45.6–50.0 years [
5,
9,
10]. It has been suggested that females may be diagnosed earlier (mean age 39.4 years) than males [
17]. The prognosis of GPP in older patients may be poorer than in younger patients due to the systemic complications of the disease, including cardiorespiratory failure and risk of infection and sepsis [
2,
6].
2.3 Genetic Markers in GPP
The etiology of GPP is not fully understood; however, the interleukin (IL)-36 pathway appears to be pivotal in the pathogenesis of the disease. The potential role of IL-36 has been supported by the identification of loss-of-function mutations in the IL-36 receptor antagonist gene (
IL36RN) and the overexpression of IL-36 cytokines in GPP skin lesions [
18]. The
IL36RN gene is responsible for suppressing proinflammatory responses triggered by IL-36α, IL-36β, and IL-36γ via the encoding of a functional IL-36Ra protein [
6]. In addition, variants of
CARD14, which encodes a keratinocyte adaptor protein, and
AP1S3, which encodes a subunit of the adaptor protein 1 complex, have also been implicated in GPP [
2,
19].
CARD14 variants are relatively rare, with some regional variability. A recent review of published evidence on the genetic basis of GPP noted that
CARD14 variations rarely present in patients with GPP alone and are more commonly found in cases of GPP with concomitant psoriasis vulgaris; however,
CARD14 variations specific to either GPP or psoriasis vulgaris have not yet been characterized [
20]. In a recent variant-screening study conducted in 863 patients with pustular psoriasis, no
CARD14 substitutions were observed among European patients with GPP, but were present in Chinese patients [
19]. A
CARD14 variant was identified in Japanese patients with both GPP and psoriasis vulgaris, but was not associated with psoriasis vulgaris alone, and was not reported in patients with GPP alone, in this population [
21].
AP1S3 variants have been reported consistently across pustular psoriasis subtypes. Over 95% of patients with variations in this gene were female, indicating that sex-specific factors may alter the penetrance of
AP1S3 variants [
19].
Recently, loss-of-function variants of myeloperoxidase gene (
MPO) that are associated with increased neutrophil accumulation and activity have been reported in some patients with GPP [
22]. A rare loss-of-function variant in
SERPINA3, which encodes serine protease inhibitor A3 (serpin A3), has also been identified in patients with GPP [
23].
Loss-of-function variants of
IL36RN have been identified in 23–37% of familial and sporadic GPP cases [
18,
24]. The frequency of
IL36RN variants shows regional differences, from 28.8% in Malaysian patients to 34.7% in European patients with GPP, and 46.8–60.5% in Han Chinese patients; one study noted that
IL36RN may be the major gene associated with the pathogenesis of GPP in the Han population in China [
5,
25]. Further analysis in the Chinese population suggested that the mechanisms of IL-36 overexpression differ between patients with GPP and those with psoriasis vulgaris, which may explain previous observations of a lack of association between
IL36RN variation and the development of psoriasis vulgaris [
13]. In patients with homozygous
IL36RN variants, the age of onset of GPP can be earlier than usual, and
IL36RN disease alleles have a dose-dependent effect on age of onset in all pustular psoriasis subtypes [
19].
While
IL36RN and
CARD14 variations are implicated in the pathogenesis of GPP, clinical experience of patients presenting with both mutations simultaneously is limited. In 2019, the first published case described a patient with heterozygous
IL36RN variation (compared with typical homozygous or combined heterozygous variation in GPP), with the authors suggesting that coexisting mutations in
IL36RN and
CARD14 may also predispose individuals to GPP [
26].
Screening of
IL36RN,
CARD14, and
AP1S3 is not routinely indicated; however,
IL36RN status is becoming increasingly recognized as a useful tool in the diagnosis of GPP [
2].
2.4 GPP in Pregnancy
Impetigo herpetiformis, or GPP during pregnancy, has a typical onset in the last trimester, and while the etiology is unclear, associations with hypocalcemia and hypoparathyroidism have been suggested in some cases [
27]. Pregnancy has been identified as a precipitating factor for flares in patients with GPP [
10], and GPP in pregnancy is associated with severe outcomes, including placental insufficiency leading to an increased risk of stillbirth, neonatal death, and fetal abnormalities [
28].