An update on generalized pustular psoriasis

ABSTRACT

Introduction: Generalized pustular psoriasis (GPP) is a rare, severe relapsing/remitting, multisystem disease that can be difficult to treat. Recent clinical, histological, and genetic evidence suggests that GPP is a distinct clinical entity from plaque psoriasis and requires a separate diagnosis. The interleukin-36 pathway appears to be central to GPP pathogenesis. As no therapeutic agents have been approved for GPP to date in the United States or Europe, the introduction of anti-IL-36 therapies may change disease management.

Areas covered: Using PubMed and Google Scholar, we reviewed the literature for articles related to GPP, psoriasis, and the genetics, pathogenesis, and treatment thereof.

Expert opinion: New therapeutic options and updated guidelines for GPP treatment are needed. Ideal agents would have rapid onset of action and rapid time to achieve disease clearance, have the ability to prevent acute flares and avert recurrence, and possess a favorable safety profile. Such therapies should be readily accessible via approval or listing on formularies. Scoring systems to establish GPP disease burden and objective outcome measures could also help with further evaluation of therapies and treatment access issues. IL-36 remains a promising target, as supported by early phase data suggesting efficacy and safety for a novel anti-IL-36 therapy.

Plain language summary

Generalized pustular psoriasis (GPP) is a rare dermatological condition; it is characterized by the sudden appearance of multiple small blisters filled with pus (called pustules) on large areas of the skin of the body, arms, and legs, that also become red and painful. The pustules are not infectious. Other symptoms may include fever, chills, and loss of appetite. These episodes are called flares, and can cause – in the most severe cases – life-threatening complications (such as heart failure, and/or serious infection) that may require emergency medical treatment. GPP can last from days to weeks, and often comes back. The cause of GPP is unknown, but specific factors are known to trigger a flare (such as taking certain medicines, or suddenly stopping steroid medicines). Problems with the immune system are likely to be important in causing GPP. The interleukin-36 pathway involves a group of proteins that act on immune cells in the skin (and other tissues). These proteins are linked to the development of GPP in some people. This article aims to provide a summary of the main features of GPP, including possible immune and genetic factors (particularly the interleukin-36 pathway), and the limitations of treatment options available to doctors.

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KEYWORDS:

• Biologics
• GPP
• generalized pustular psoriasis
• IL-36
• IL-36 receptor antagonist
• von Zumbusch

1. Introduction

Generalized pustular psoriasis (GPP) is a severe multisystem disease characterized by the sudden and widespread eruption of superficial sterile pustules [1,2]. It may or may not be preceded by a history of plaque psoriasis, and the systemic complications of GPP – when present – have the potential to be life-threatening, particularly in older patients (e.g., bacterial infection [3], cardiorespiratory failure [4]). Although children and infants can be affected by GPP, cases usually occur in adults. GPP is a rare condition, and the prevalence is greater in Asian than Caucasian populations (7.46/million in Japan versus 1.76/million in France) [5,6]. There is no standard treatment for GPP, and guidance often follows that for plaque psoriasis treatment. No therapeutic agents have been approved for GPP treatment in the United States or Europe to date, although both oral and conventional biologic agents have been used to successfully treat GPP. Several biologic agents have been approved in Japan for use in the treatment of GPP, including monoclonal antibodies against interleukin (IL)-17 (secukinumab, ixekizumab, and brodalumab [7]) and IL-23 (guselkumab [8]). Targeted biologic therapies have had a profound effect on the clinical management of individuals with plaque psoriasis (moderate and severe disease) [9], although their use in GPP has been more limited. This report provides an overview of GPP, including the features of GPP and related pustular skin conditions, a review of proposed key mediators in the immunopathogenesis of GPP, and a discussion of the current options for GPP treatment and their limitations. Literature was retrieved using Boolean searches for English language articles in PubMed and Google Scholar, and including terms related to GPP, psoriasis, and the genetics, pathogenesis, and treatment thereof. The reference lists from retrieved articles were also considered. Additional data were obtained from websites of the US Food and Drug Administration (FDA) and from websites pertaining to individual therapeutic agents of interest.

2. Clinical presentation

Japanese guidelines (2018) diagnose GPP on the basis of the following primary parameters (definitive diagnosis if all four parameters are present; suspected diagnosis with two or three parameters): a) systemic symptoms such as fever and fatigue; b) systemic or extensive flushing accompanied by multiple sterile pustules that sometimes merge to form lakes of pus; c) neutrophilic subcorneal pustules histopathologically characterized by Kogoj’s spongiform pustules; and d) repeated recurrence of the above-stated clinical and histological findings [7]. European guidelines (2017) define GPP as primary, sterile, macroscopically visible pustules on nonacral skin (excluding cases where pustulation is restricted to psoriatic plaques) that can occur with or without systemic inflammation, and with or without plaque psoriasis, and can be either relapsing (more than one episode) or persistent (more than 3 months) [2]. Laboratory test findings in patients with GPP commonly include elevated C-reactive protein, leukocytosis and neutrophilia, and liver function abnormalities [4,10]. GPP may be classified into the following types: acute GPP (von Zumbusch variant; representing more than 50% to more than 90% of adult cases [3,11,12]), pustular psoriasis of pregnancy (previously referred to incorrectly as ‘impetigo herpetiformis’ [13]), and infantile/juvenile pustular psoriasis [14]. Pustular psoriasis may occur in localized forms, including palmoplantar pustular psoriasis and acrodermatitis continua of Hallopeau (ACH) [14]. Some clinicians also consider subcorneal pustular dermatosis (Sneddon–Wilkinson syndrome) to be a localized variant of pustular psoriasis [15]. In addition, acute generalized exanthematous pustulosis (AGEP) shares many features in common with GPP [16], and has been described as a drug-induced form of pustular psoriasis, although the clinical features, treatments, course, and triggers differ substantially from GPP [4]. The main clinical and histological features of GPP are summarized in Table 1 [4,13,14,17–20] and Figure 1a [21]. Skin lesions typically observed in patients with GPP are shown in Figure 1b. Recently, GPP cases with autoinflammatory patho-mechanisms have been classified as an ‘autoinflammatory keratinization disease’ (AiKD) [22].

Figure 1. Microscopic and macroscopic features of GPP. Histopathology of psoriasis. (a) Psoriasis vulgaris characteristically shows acanthosis, parakeratosis, and dermal inflammatory infiltrates. (b) In pustular psoriasis, acanthotic changes are accompanied by epidermal predominantly neutrophilic infiltrates, which cause pustule formation. (Reproduced from “Psoriasis Pathogenesis and Treatment” by Adriana Rendon and Knut Schäkel [Int. J. Mol. Sci. 2019; 20: 1475; http://dx.doi.org/10.3390/ijms20061475] licensed under CC-BY 4.0). (c) Macroscopic features of GPP. (Reproduced with permission from DermNet New Zealand Trust, Hamilton, New Zealand). GPP: generalized pustular psoriasis

Table 1. Main features of GPP

	Presentation	Histopathology	Etiology and pathoimmunology
Acute GPP (von Zumbusch) [4,14,17]	Rapid & widespread formation of small sterile pustules with inflammation & erythema; occur on trunk & limbs (rarely on the face) Pustules often expand & coalesce into lakes of pus; pustulation lasts days to weeks ± Subungual pustules ± fissured tongue ± geographic tongue ± conjunctivitis Systemic symptoms commonly include fever (up to 40°C/104°F), chills, malaise, nausea, & pain Leukocytosis (up to 40,000/μL), elevated ESR, increased plasma globulins, decreased albumin & calcium, ± elevated BUN & creatinine, ± elevated AST & ALT; bacterial cultures are negative in the absence of secondary infection Possible complications include secondary infections (e.g., pneumonia, sepsis), neutrophilic cholangitis, aseptic respiratory distress syndrome, & cardiorespiratory failure	Overall epidermal architecture similar to plaque psoriasis (i.e., parakeratosis, rete ridge elongation, thinning suprapapillary epidermis) Superficial dermal infiltrate of mononuclear cells, with neutrophils migrating from papillary capillaries to the epidermis, & formation of subcorneal macropustules (spongiform pustules of Kogoj = characteristic sign of GPP)	Precipitating factors include infection, stress, corticosteroids (treatment & withdrawal) Mutations were identified in IL36RN, CARD14, and AP1S3 in some GPP patients, leading to dysregulation of pro-inflammatory pathways [18–20]
Pustular psoriasis of pregnancy [13,14]	Eruption of sterile pustules with annular or polycyclic erythematous areas; often begins at skin folds (of breasts & axillae) & spreads outward; does not usually involve face/palms/soles of feet Systemic symptoms include fever, chills, malaise, nausea, & joint pain Leukocytosis with neutrophil predominance, elevated ESR, decreased albumin & calcium, ± decreased vitamin D	As GPP	Commonly occurs in third trimester of pregnancy Associated with poor neonatal outcomes Dermatological symptoms often resolve rapidly following delivery; may recur during a subsequent pregnancy
Infantile/juvenile pustular psoriasis [4,14]	Annular-type common, lesions mainly on the trunk Systemic involvement may occur Leukocytosis with neutrophil predominance, elevated ESR	As GPP	Precipitating factors include infection, vaccination, corticosteroid withdrawal Etiology & pathogenesis currently unknown; possible genetic component

ALT: alanine transaminase; AP1S3: adaptor protein complex 1 subunit sigma 3 gene; AST: aspartate transaminase; BUN: blood urea nitrogen; CARD14: caspase-activating recruitment domain member 14 gene; ESR: erythrocyte sedimentation rate; GPP: generalized pustular psoriasis; IL36RN: interleukin 36 receptor antagonist gene.

GPP is a relapsing and remitting disease with a highly variable clinical course, and symptom severity may vary with each flare episode in an individual patient [17]. Recurrence of GPP flares may occur years after the initial diagnosis; conversely, patients may experience multiple flares per year. Although idiopathic in many cases, GPP flares may be caused by internal and external triggers, including infection [1,3,11], pregnancy [11], withdrawal of corticosteroids [11], and initiation of other drugs (e.g., ustekinumab [23], some tumor necrosis factor [TNF] antagonists [24]). In some cases of drug-related disease, it may be difficult to distinguish between GPP and AGEP, as the latter also presents as a disseminated pustular eruption. However, certain medications are strongly associated with AGEP, including pristinamycin, ampicillin/amoxicillin, quinolones, anti-infective sulfonamides, terbinafine, and diltiazem [25]. In contrast, the withdrawal of systemic corticosteroids in a patient with plaque psoriasis is a leading cause of GPP. Complications and morbidity from GPP may arise for a variety of reasons, including secondary bacterial infection, hypoalbuminemia (secondary to loss of plasma proteins into the tissues), hypocalcemia, renal tubular necrosis (secondary to oligemia), liver damage (secondary to oligemia and neutrophilic cholangitis), and malnutrition; furthermore, untreated patients have an increased risk of cardiorespiratory failure [4]. Providing treatment is initiated promptly, the prognosis for most patients with GPP is generally good; however, elderly patients may have poorer outcomes [4]. Mortality data from studies of patients with GPP are limited, but rates of 3% [3] and 7% [11] have been reported. As GPP often presents in individuals with existing/history of plaque psoriasis (reported in more than 65% of GPP cases [11,26]), GPP has been categorized as a variant of plaque psoriasis. However, recent clinical, histological, and genetic evidence suggests that GPP is a distinct clinical entity and requires a separate diagnosis [2,7,27–30].

3. Pathoimmunology

The pathoimmunology of GPP is not yet fully understood. Currently suggested pathoimmunogenetic mechanisms for GPP (and plaque psoriasis) are complex, and a detailed description is beyond the scope of this report; however, these pathways are reviewed comprehensively by Johnston and colleagues [29], Furue and colleagues [31], and Ogawa and colleagues [32]. A summary of the main points is provided below.

The IL-36 cytokines IL-36α, IL-36β, IL-36γ, and IL-36 receptor antagonist (IL-36Ra), which are part of the IL-1 family, are expressed in a variety of cell types, including keratinocytes. Binding of IL-36α, IL-36β, or IL-36γ to the IL-36 receptor (IL-36R) leads to the stimulation of inflammatory responses, inducing the release of chemokines that promote activation of neutrophils, macrophages, dendritic cells, and T cells. Gene IL36RN encodes protein IL-36Ra, which suppresses the pro-inflammatory responses triggered by IL-36α, IL-36β, and IL-36γ. Mutation of IL36RN leads to functional impairment of IL-36Ra, caused by decreased messenger RNA/protein expression or structural changes to the amino acid sequence, and subsequent enhancement of the downstream inflammatory cascade, i.e., loss-of-function mutation of IL36RN leads to exaggerated IL-36 signaling [18,33]. In GPP, loss-of-function mutations of IL36RN were identified in both familial [18] and sporadic [33] cases. Subsequent studies found that IL36RN mutations were often present in patients with GPP, particularly in those individuals without associated plaque psoriasis [34,35]; the reported frequency of IL36RN mutation in GPP cohorts ranges from 23% to 37% [34–37]. The disease observed in patients with acute GPP and IL36RN mutations resulting in reduced IL-36Ra activity was named DITRA (deficiency of IL-36Ra); high-grade fever and general malaise were noted to occur during a DITRA flare [18]. The influence of IL36RN mutation status on disease severity was reported in a meta-analysis of 233 patients with GPP, in which the presence of recessive IL36RN alleles (found in 49/233 [21%] cases) was associated with early disease onset (17 ± 2.4 years vs 33 ± 1.5 years in those without pathogenic IL36RN alleles; P = 5.9 x 10^-7), systemic inflammation (83% vs 56%; P = 1.5 x 10^-3), and absence of concurrent plaque psoriasis (36 vs 69%; P = 5.0 x 10^-4) [35]. Other gene mutations have been identified in different groups of patients with GPP (and related conditions) that lead to an enhanced inflammatory cascade and the recruitment of neutrophils and macrophages. These include mutations in CARD14 encoding caspase-activating recruitment domain member 14 and AP1S3 encoding adaptor protein complex 1 subunit sigma 3 (Supplementary Table 1) [18,20,33,34,38–45].

Recent gene expression analyses have demonstrated that the transcriptome of GPP shares features in common with that of plaque psoriasis, but is inclined more toward innate immune inflammation (i.e., immediate, nonspecific responses to antigen) [29,46], whereas adaptive (i.e., antigen-specific) immune responses appear to have a more central role in plaque psoriasis [29]. Functional IL-36R activation and loss-of-function mutation of its antagonist IL-36Ra are believed to be central to the pathogenesis of pustular psoriasis (Figure 2 and online video animation), while the TNF-α/IL-23/IL-17/IL-22 axis drives plaque psoriasis (reviewed in [29,31,32]). For comparison, acute forms of psoriasis are driven by type 1 interferons [47]. However, these pathways are closely linked, and active ‘cross-talk’ between the two may result in a progressive cycle of inflammation (reviewed in [31]). Microarray analyses profiling gene expression in skin biopsy samples (GPP, N = 28; plaque psoriasis, N = 12) found that both GPP and plaque psoriasis lesions overexpressed IL-17A, TNF-α, IL-1, IL-36, and interferons (IFNs), but GPP lesions had higher expression levels of IL-1β, IL-36α, and IL-36γ, with lower levels of IL-17A and IFNγ than plaque psoriasis lesions [29]. GPP lesions also had greater expression of neutrophil chemokines (CXCL1, CXCL2, and CXCL8 [IL-8]) and greater enrichment of neutrophil and monocyte transcripts when compared with plaque psoriasis lesions [29]. Elevated expression of IL-36 in GPP was localized to keratinocytes surrounding neutrophilic pustules [29].

Figure 2. Pathoimmunology of GPP. (a) Role of IL-36 cytokines. (b) Role of IL-36 receptor antagonist. (c) Role of IL36RN gene mutation. (d) Proposed central mediators in GPP [29,31]. (See also online video animation)

GPP: generalized pustular psoriasis; IL: interleukin; IL36RN: IL-36 receptor antagonist gene; TNF: tumor necrosis factor.

A further gene expression study using biopsies from pustular skin diseases (GPP, N = 30; palmoplantar pustulosis, N = 17; and AGEP, N = 14) reported common alterations in expression of genes affecting neutrophil chemo-attraction (including IL36RN and IL8), as well as the novel shared feature of upregulation of the six-transmembrane epithelial antigens of prostate (STEAP) proteins STEAP1 and STEAP4, which correlated with overexpression of pro-inflammatory cytokines, including IL-1, IL-36, CXCL1, and CXCL8 [46]. Interestingly, STEAP1 and STEAP4 were not overexpressed in samples from patients with plaque psoriasis. Further analyses suggested that STEAP1 and STEAP4 may promote neutrophil chemotaxis in pustular psoriasis, possibly by stimulating the production of neutrophil-activating cytokines (e.g., IL-36 group, CXCL1, and CXCL8) [46].

IL-17 is one of the main cytokines produced by T-helper (Th) 17/Th1 cells, which have a key role in the pathogenesis of plaque psoriasis. IL-17A is a potent inducer of tissue inflammation and neutrophil recruitment [48], and is assumed to have a role in GPP pathogenesis [30]. Although activation of Th17/Th1 signaling is common to both GPP and plaque psoriasis, expression levels of Th17-/Th1-related cytokines (such as IL-17A, IL-22, IL-23p19, IFNγ, and IL-18) were observed to be significantly increased in plaque psoriasis lesions compared with GPP lesions [29]. Studies of palmoplantar pustular psoriasis and palmoplantar pustulosis have also observed increased gene expression of IL-17 without an increase in IL-23 [49,50]. These various data provide the rationale for the development of newer therapies (biologics) to target pro-inflammatory pathways in GPP [29].

4. Current treatments and their limitations

Treatment options for GPP are summarized in Table 2 [7,13,14,17,51–58], and benefits and limitations of the various treatment classes are summarized in Table 3 [4,17,29,30,51,53,54,56,57,59–79]. It should be reiterated that no GPP-specific therapeutic agents have been approved in the United States or Europe to date. There is also no standard guidance for GPP therapy; treatment is informed by the extent of involvement, disease severity, and the presence of any underlying risk factors [70]. Treatment for GPP often follows the existing guidance for plaque psoriasis. US guidance on GPP treatment from the National Psoriasis Foundation Medical Board was published in 2012 [70], prior to the availability of many of the targeted biologic therapies now used in psoriasis (plaque or pustular types). The rarity of GPP cases and the relapsing-remitting nature of this disease make it difficult to initiate randomized controlled clinical trials to investigate treatment efficacy and safety; thus, available data originate mainly from case reports and small single-arm studies.

Table 2. Treatment of GPP

Treatment	Details	Other information
Adults
Systemic therapy
Acitretin [14]	Oral; 0.75–1.0 mg/kg/day; maintenance: 0.125–0.25 mg/kg/day for several months	Isotretinoin may be used as an alternative (shorter half-life); however, it is only available under US restricted distribution program, iPLEDGE®
Cyclosporine [14]	Oral; 3.5–5 mg/kg/day; if adequate response, taper down by 0.5 mg/kg every 2 weeks	Rapid onset; best for severe acute disease Monitor patient’s BP and renal function, and check for immunosuppressive effects
Methotrexate [14]	Oral, IM, or IV; 5–15 mg/week, increased by 2.5 mg/week until response; start at 7.5 mg/week for patients aged >70 years; maximum 25 mg/week	Slow onset of action
Anti-TNF-α agent
Infliximab [7]	IV; 5 mg/kg at weeks 0, 2, and 6, then every 8 weeks as needed	Rapid onset of action; good for severe acute disease and extensive disease
Adalimumab [7]	SC; 80 mg weekly for 2 weeks, then 40 mg every 2 weeks
Etanercept [14]	SC; 50 mg biweekly for 3 months, then 50 mg weekly	Possible worsening of pustular psoriasis, especially with comorbid RA or IBD
Corticosteroids, oral	Prednisone 30–60 mg/day; taper dose following symptom improvement	May be considered if other treatments are not possible; must be used with caution and with gradual dose tapering as rapid withdrawal may induce pustular flare
Topical therapy
Corticosteroids [14]	Topical; applied twice daily
Calcipotriene (+ systemic agent) [14]	Topical; 5 μg/g applied twice daily
Tacrolimus (+ systemic agent) [14]	Topical; 0.01%–0.1% applied twice daily
PUVA [14]	Topical; high-intensity (1.0–5.0 J/cm^2) UVA light whole-body irradiation 2 hours after topical application of 0.6 mg/kg of 8-MOP, treatments 4 times weekly until clearing of skin lesions; maintenance therapy of 2 treatments weekly, gradually reduced to once weekly or less	Not for acute inflammatory forms of psoriasis
TAC ointment + total body wet wraps; whirlpool treatments [14]	Topical; standard dosing	For symptomatic treatment to decrease lesion crusting, scaling, and discomfort
Other biologic therapy
Anti-IL-1 agents
Anakinra [14]	SC; 100 mg daily
Canakinumab [51]	Body weight >40 kg: SC; 150 mg every 4 weeks, can increase to 300 mg every 4 weeks if clinical response inadequate
Gevokizumab [14]	SC; 60 mg every 4 weeks for 12 weeks
Anti-IL-17 agents
Secukinumab [7,14]	SC; 300 mg weekly for 3 weeks, then 300 mg every 4 weeks
Brodalumab [7]	SC; 210 mg at weeks 0, 1, & 2, then 210 mg every 2 weeks
Ixekizumab [7]	SC; 160 mg at week 0, then 80 mg at weeks 2, 4, 6, 8, 10, & 12, then 80 mg every 4 weeks
Anti-IL-23 agents
Guselkumab [52,53]	SC; 50 mg at weeks 0 & 4, then 50 mg every 8 weeks [52]; or 100 mg at weeks 0 & 4, then 100 mg every 8 weeks [53]
Ustekinumab [7,14]	SC; 45 mg at weeks 1, 4, & 16; maintenance with 45 mg every 12 weeks
Other therapy
Granulocyte and monocyte adsorption apheresis [14]	Extracorporeal; 60-minute session twice weekly (total of 7 to 8 sessions)
Dapsone [51,54]	Oral; initial dose 25–100 mg daily, then titrated to response 100–150 mg daily as tolerated Topical; 5% gel may be used instead	Check FBC and G6PD prior to treatment initiation
Children
Systemic therapy
Acitretin [55]	Oral; severe or recalcitrant disease, ≤0.5–1 mg/kg/day	Skeletal toxicity potential risk; teratogenicity ∴contraindicated in young females of reproductive potential
Acitretin + prednisone [14]	Oral; standard dosing	For acute disease
Cyclosporine [55]	Oral; severe or recalcitrant disease, 1.5–5 mg/kg/day for >6 weeks; taper to lowest dose needed for clinical disease control	Clinical effects usually observed within 4–8 weeks Monitor patient’s BP and renal function, & check for immunosuppressive effects
Methotrexate [55]	Oral; severe or recalcitrant disease, 0.2–0.7 mg/kg/week; may need to escalate dose to achieve clinical benefits, followed by slow tapering to maintenance dose	Long-term use linked to hepatotoxicity
Anti-TNF-α agents		Limited data available; etanercept has majority of reports for use of these agents in childhood psoriasis [55]
Infliximab [55]	IV; 3–5 mg/kg at weeks 0, 2, and 6, then every 8 weeks
Adalimumab [55]	SC; 0.8 mg/kg (maximum 40 mg) at weeks 0 and 1, then every 2 weeks
Etanercept [55]	SC; 0.8 mg/kg/week or 0.4 mg/kg twice weekly; maximum 50 mg per week	Approved indications include treatment of patients aged ≥4 years with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy [57]
Topical therapy
UVB [55]	Topical; standard dosing	May be combined with systemic or other topical treatment to reduce cumulative UVB dose & potential skin cancer risk Unsuitable for small children due to short-term adverse effects (dry skin, itching, erythema, herpes simplex activation) & difficulties associated with recurrent treatment visits & remaining inside UV chamber
Pregnancy
Systemic therapy			Risk category*
Cyclosporine [13]	Oral; 2–3 mg/kg/day	Not usually associated with increased risk of adverse effects during pregnancy at this dose; do not use while breastfeeding; monitor BP & renal function, & check for immunosuppressive effects	C [14]
Corticosteroids, oral [13]	Oral; mild disease, corticosteroid 15–30 mg/day; severe disease, prednisone or prednisolone 30 mg/day to maximum 60–80 mg/day (caution at higher doses, as can lead to reduced fetal activity on fetal monitoring)	Use with caution: gradual dose tapering, as rapid withdrawal may induce pustular flare; may be used with cyclosporine for severe cases	C/D Use lowest dosage possible [14]
Anti-TNF-α agents		Limited data available; greater number of reports of pregnancies exposed to infliximab than either adalimumab or etanercept [58]
Infliximab [13,14]	IV; 5 mg/kg at weeks 0, 2, & 6 [56]	Rapid onset, effective for acute disease; limit use to first 30 weeks’ gestation [13]	B [14]
Topical therapy
UVB [14]	Topical; 69 mJ/cm^2 3 times weekly increased at 10% increments with each treatment for sessions 1–34 and by 5% increments for treatments 35–42	Often effective when resistant to topical corticosteroids	Safe [14]
Corticosteroids [14,17]	Topical; mild disease, standard dose		Unknown Use lowest strength possible [14]

*Lettering system per pre-2015 FDA pregnancy risk categories (revised pregnancy and lactation labeling has yet to be applied to all medications [13]); category B = animal reproduction studies failed to demonstrate risk to fetus and there are no adequate/well-controlled studies in pregnant women; category C = animal reproduction studies have shown an adverse effect on fetus and there are no adequate/well-controlled studies in pregnant women, but potential benefits may warrant use of drug in pregnant women despite potential risks; category D = positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of drug in pregnant women despite potential risks.

8-MOP: 8-methoxypsoralen; BP: blood pressure; FBC: full blood count; FDA: US Food and Drug Administration; G6PD: glucose-6-phosphate dehydrogenase; GPP: generalized pustular psoriasis; IBD: inflammatory bowel disease; IL: interleukin; IM: intramuscular; IV: intravenous; PUVA: psoralen plus UVA; RA: rheumatoid arthritis; SC: subcutaneous; TAC: triamcinolone acetonide; TNF: tumor necrosis factor; UVA: ultraviolet-A; UVB: ultraviolet-B.

Table 3. Benefits and limitations of treatment classes used in GPP

Treatment type	Agents	Mechanism of action	Benefits	Potential safety issues
Retinoid (oral)^a	Acitretin	Mechanism of action in psoriasis is not fully understood Believed to normalize keratinization and epidermal cell proliferation; may suppress the production of pro-inflammatory cytokines, including TNF-α, IL-1, & IL-6 [17]	Obtained via health insurance Onset of action in weeks	Teratogenic; contraindicated during pregnancy [76] Long-term treatment may be associated with osteoarticular symptoms [76] and may adversely affect bone growth in children [76]
Calcineurin inhibitor	Cyclosporine	Decreases production of inflammatory cytokines by T cells via inhibition of calcineurin [66]	Suitable for severe, acute disease due to the fast onset of action [70]	FDA pregnancy category C^b Not recommended for long-term use due to potential forhypertension & renal dysfunction [17,77]
Anti-TNF-α	Adalimumab [59]; etanercept [57]; infliximab [56]	Antagonist of TNF-α, a cytokine that is upregulated in GPP lesions [29]	Infliximab reported to have a rapid onset of action (pustule clearance 1–3 days) [30]	Increased risk of serious infections (including tuberculosis, bacterial sepsis, invasive fungal infections, & infection by invasive opportunistic pathogens) [56,57,59] Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with these agents [56,57,59]
Anti-IL-1/IL-36	Anakinra [60]; canakinumab [61]; gevokizumab	Antagonist of IL-1 receptor (anakinra) or IL-1β (canakinumab & gevokizumab) Inhibits the IL-1/IL-36 inflammatory axis	Sustained clinical efficacy demonstrated in case reports of GPP [30,51]	Increased risk of infections [60,61] Injection site reactions [60,61] Decreased neutrophil count has been reported with anakinra [60]
Anti-IL-17	Secukinumab [62]; brodalumab [63]; ixekizumab [64]	Antagonist of IL-17, a cytokine that mediates neutrophil migration	Secukinumab was highly effective in patients with plaque psoriasis [71] and was superior to ustekinumab in a subsequent head-to-head study [72] Sustained clinical efficacy demonstrated in case reports and several small open-label phase 3 trials in GPP [30,51]	Increased risk of serious infections [62–64] Inflammatory bowel disease has been reported [62–64] Suicidal ideation and behavior have been reported with brodalumab [63]
Anti-IL-23	Guselkumab [53]; ustekinumab [65]	Antagonist of IL-23, a pro-inflammatory cytokine Ustekinumab also inhibits IL-12, another pro-inflammatory cytokine	Sustained clinical efficacy demonstrated in case reports of GPP [30,51]	Increased risk of infection [53,65] Ustekinumab may increase risk of malignancy [65]
Anti-neutrophil	Dapsone	Mechanism of action is not fully understood Believed to inhibit neutrophil myeloperoxidase & also prevent neutrophil recruitment [67]	Clinical efficacy demonstrated in case reports of GPP [54]	Methemoglobinemia has been reported [78] Hemolytic anemia has been reported [78]
Other drugs	Methotrexate	Inhibits differentiation and proliferation of the epidermis May also inhibit immune cells (including macrophages, neutrophils, lymphocytes)	Recommended if patient unresponsive/intolerant to retinoids [70]	Contraindicated during pregnancy; abortifacient, mutagenic, teratogenic Drug use should be interrupted for at least 3 months’ preconception in men and women Potential hepatotoxicity and hematologic toxicity Onset of action = weeks
	Corticosteroids	Activates glucocorticoid receptor, resulting in enhanced transcription of anti-inflammatory genes and decreased transcription of inflammatory genes [68]	Oral corticosteroids can be used for short-term relief of symptoms during acute flares Body wraps can be used to promote penetration when corticosteroids are applied topically	Systemic corticosteroids = FDA pregnancy risk category C^b Withdrawal of topical or systemic corticosteroid may precipitate GPP flare [70] Possible increased risk of cleft palate when used during first trimester of pregnancy [79]
Phototherapy	PUVA; Narrow-band UVB	Psoralen sensitizes the skin to UVA; penetration through epidermis & dermis Narrow-band UVB penetration through epidermis only Phototherapy induces apoptosis of T cells, inhibition of cytokine release, decreased Th17/Th1 inflammatory response, & decreased keratinocyte proliferation [69]	Clinical efficacy demonstrated in case reports of GPP [73–75] When used, PUVA is typically started following patient stabilization with acitretin or cyclosporine; not recommended in acute GPP [4]	Oral psoralen contraindicated during pregnancy = FDA pregnancy category C^b; topical psoralen safety in pregnancy not established Potential long-term side effects may include photoaging & an increased risk of nonmelanoma skin cancer Possible logistical challenges of multiple clinic visits for treatment [4]

^aIsotretinoin is available under US restricted distribution program iPLEDGE®; etretinate was withdrawn from the US market.

^bCategory C = defined in Table 2 footnote.

FDA: US Food and Drug Administration; GPP: generalized pustular psoriasis; IL: interleukin; PUVA: psoralen plus UVA; Th: T helper cell; TNF: tumor necrosis factor; UVA: ultraviolet-A; UVB: ultraviolet-B.

Systemic therapy in adults with GPP typically includes oral retinoids (acitretin), cyclosporine, methotrexate, or an appropriate biologic agent with a rapid speed of onset. In Japan, other types of biologics are approved for the treatment of GPP, including antagonists of IL-17 (secukinumab, ixekizumab, and brodalumab [7]) and IL-23 (guselkumab [8]). These and other biologics used in GPP are discussed below. It should be noted, however, that paradoxical induction of GPP has been reported with some biologics [23,24,80]. Retinoids provide effective therapy in many GPP cases, but they also have dose-dependent adverse effects. Oral retinoids are contraindicated in women who are pregnant or who may become pregnant [76]. A recent systematic review that identified 101 published adult cases of patients with GPP (predominantly acute GPP/von Zumbusch type) who had received targeted immunotherapy reported that the most common treatment agents applied before or concomitantly with targeted immunotherapy were cyclosporine and retinoids (including acitretin, etretinate, isotretinoin, and bexarotene; however, it should be noted that only acitretin is currently approved by the FDA for systemic use in psoriasis) [30], followed by methotrexate and systemic corticosteroids. Case reports of GPP treatment using other agents, such as the antineutrophil agent dapsone (five cases treated) [54] and the small molecule (phosphodiesterase-4 inhibitor) apremilast (one case treated) [81], have also been published. Published data on the use of small molecules in GPP are generally lacking; although agents such as Janus kinase (JAK) inhibitors are in clinical development as a possible treatment for plaque psoriasis (reviewed in [82]).

Second-line therapy in adults with GPP may include combination therapy of a biologic plus nonbiologic agent. Topical treatments (e.g., corticosteroids, calcipotriene, and tacrolimus) may be useful as an adjunct to systemic therapy or as first-line therapy for mild (or localized) disease. Oral corticosteroids may be considered in GPP if other treatment choices are not possible, but these agents should be used with caution and with gradual tapering of medication, as rapid withdrawal may induce a pustular flare. Psoralen ultraviolet (UV)-A phototherapy may be considered as second-line treatment in adults (although availability may be limited) but it is not recommended for acute forms of pustular psoriasis, and is not considered to be safe during pregnancy. Granulocyte and monocyte apheresis have also been utilized successfully in some refractory cases of GPP [83,84].

Recommendations for systemic therapy for GPP in childhood are similar to those for adults, and include acitretin (monotherapy, or in combination with oral prednisone in severe disease), methotrexate, and cyclosporine. None of these agents are FDA approved for psoriasis treatment in children due to the lack of randomized controlled trials data in this age group [55]. Oral retinoids are contraindicated in young females of reproductive potential. Second-line therapy for GPP in children may include anti-TNF-α agents [85] or UV-B phototherapy.

Data for the use of systemic therapy for GPP in pregnant and lactating females are also limited. Treatment options include cyclosporine (at a reduced dose), oral corticosteroids, topical agents, and phototherapy with narrow-band UV-B [13]. Controlled clinical data are lacking on the safety of biologics during pregnancy in patients with psoriasis [58]; however, these agents are generally classified as FDA pregnancy risk category B (under the pre-2015 lettering scheme [86]) [13]. Currently, anti-TNF-α agents can be used during the first half of pregnancy (due to active transplacental transport after gestational week 22), and longer-term use may be considered on an individual patient basis depending upon disease severity [58]. Treatment must balance the possible adverse effects of drug therapy with the serious and potentially life-threatening consequences of GPP to the mother and fetus.

Case reports/series and some small open-label trials have been published on newer biologic therapies that target cytokines associated with GPP pathoimmunology (reviewed recently by Boehner et al. [30] and Zhou et al. [51]). GPP case reports of agents targeting the IL-1–/IL-36–chemokine-neutrophil axis include the recombinant IL-1 receptor antagonist anakinra [87,88] and the anti-IL-1β monoclonal antibodies canakinumab [89] and gevokizumab (in clinical development; not yet FDA approved) [90]. Further anti-IL-36 agents are in early clinical development, including ANB019 (anti-IL-36R) [91], and BI 655130 (anti-IL-36R) [92]. GPP case reports describe the use of the monoclonal antibody ustekinumab [93,94] targeting the shared p40 subunit of IL-12 and IL-23, and an open-label phase 3 study reported treatment success in 7/9 patients with GPP receiving guselkumab [52], which also targets IL-23 by binding to the p19 subunit. Open-label phase 3 studies reported treatment success in 10/12 patients with GPP receiving the monoclonal antibody secukinumab (anti-IL-17A) [95], 11/12 patients with GPP receiving brodalumab (anti-IL-17RA) [96], and 3/5 patients with GPP receiving ixekizumab (anti-IL-17A) [97,98]. Secukinumab has also been used to treat a case of refractory juvenile GPP [99]. Although these reports describe positive clinical outcomes (i.e., skin clearance, disease remission for varying periods, and few significant adverse events) for patients with GPP using the various biologic agents, the data are limited by the small number of patients, lack of control groups, potential bias in publishing only positive therapeutic results, and many of the studies having been carried out in Japanese populations [30]. Furthermore, none of the GPP clinical trials cited above studied treatment efficacy in acute flares, but rather assessed chronic GPP using an open-label design and with the primary endpoint at 16 months or earlier. Additional research into these new biologics is needed for GPP involving larger-scale, randomized controlled clinical trials with participants from different ethnicities to provide robust efficacy and safety data. A number of clinical trials investigating the use of biologic therapies in GPP have been completed recently, and several more are ongoing (Supplementary Table 2).

5. Expert opinion

GPP is a serious and potentially life-threatening condition that must be diagnosed accurately and treated quickly. GPP adversely affects every aspect of the patient’s life during disease flare-up. The condition is painful and distressing; affected skin is covered in sterile pustules, and any contact with clothing or bedding often causes staining with blood and pus. Additionally, the skin loses all protective function, and the risk of infection (especially bacterial infection) is increased, which may be a particular issue when the patient is in the hospital. Optimal treatment for GPP would offer both a rapid onset of action for the management of acute disease flares, and a rapid time to achieve complete disease clearance. Speed of action is vital to minimize disease severity and duration of complications, and decrease the overall disease burden for the patient. Effective long-term maintenance therapy is also needed to prevent repeated GPP flares.

There are several key weaknesses in the current clinical management of GPP. The first issue is the lack of recent specific guidelines for GPP management in the United States and Europe; however, updated guidelines on GPP pathogenesis and treatment were published recently (September 2018) by the Japanese Dermatological Society [7]. Secondly, the current choice of treatments for GPP is limited, and the options available generally follow what is used for plaque psoriasis. There is a profound need for GPP-specific therapeutic agents to be licensed in the United States and Europe, as are now available in Japan. Future research should include potential differential treatment responses between ethnic groups to current and novel therapies as they become approved and available in different regions. Robust efficacy data to guide treatment choices in GPP are also lacking – this applies to both conventional agents and newer therapies, such as biologics. Stronger evidence to support the use of biologics might then facilitate more rapid patient access to these medical therapies. Time to efficacy data are of particular importance for any GPP therapeutic agent being investigated, as rapid onset of action is critical in GPP patient management. There are also problems in finding effective treatments for patients with refractory disease. However, generating meaningful GPP clinical trial data is difficult, as the rarity of this condition makes it problematic to recruit sufficient numbers of patients. Furthermore, the relapsing/remitting nature of GPP and the unpredictability of acute flares present a challenge for clinical study design. Current treatment options in GPP may also be limited by other factors, such as agent-specific safety concerns. For example, retinoids are contraindicated in pregnancy and risk of pregnancy, while the risk of malignancy or infection may be increased in agents with immunosuppressive effects. With the latter, it may also be necessary to perform screening tests for certain infections (e.g., hepatitis or tuberculosis) prior to gaining access to the desired agents, which may delay GPP treatment.

Additionally, initiating treatment with newer therapies, such as biologics, may be hindered by issues in obtaining payer approval and/or prior authorization. There is a tendency for clinicians to initiate therapy with retinoids (unless contraindicated) or cyclosporine, as these agents are more accessible; however, biologics may offer clinical benefits for GPP, such as faster reduction of symptoms and a more favorable safety profile. Therapies for GPP that are readily available and approved or listed on formularies are required. To expedite future drug development, the question of whether GPP could be approached as an orphan disease may also be considered. Improved understanding of the pathogenesis of GPP could help to identify potential new therapeutic targets. The ongoing Pustular Psoriasis Elucidating Underlying Mechanisms (PLUM) study is investigating the genetic causes of GPP and biomarkers associated with the disease. The PLUM study may also help in the quest for personalized medical treatment, as targeted therapies could be appropriately prescribed for an individual instead of the ‘try-it-and-see’ approach currently in use. The localized forms of pustular psoriasis (palmoplantar pustular psoriasis, ACH), which present more frequently in the clinic than GPP, may also help in the search for an effective GPP treatment. Currently, IL-36 seems to be a promising target for GPP treatment and, possibly, also for localized pustular psoriasis. In addition, there is a requirement for objective outcome measures that are tailored to assess the clinical features of GPP (e.g., changes in overall erythema, pustules, number of lesions, body surface area affected, disease severity, etc.) that could facilitate comparisons between different therapies. A scoring system to establish disease burden in GPP could also help with treatment access issues, rather than using the Psoriasis Area and Severity Index (PASI). A recent GPP study report evaluated patients using adaptations of PASI [100] and the Investigator’s Global Assessment (IGA) [101]. The Generalized Pustular PASI (GPPASI) replaces the induration component with a pustule component, while the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) is a clinical assessment of the severity of pustules, erythema, and scaling of GPP lesions [92]. These tools may prove useful in future GPP studies.

It is anticipated that the results from clinical trials investigating novel therapies – such as IL-36 inhibitors and other targeted biologics – will bring new treatment options and provide much-needed data on long-term maintenance of efficacy, safety, and the impact of withdrawal/re-treatment with these newer agents. The importance of targeting IL-36R signaling in GPP is supported by a recent phase 1 study (N = 7) that reported good efficacy and safety was shown by anti-IL-36R agent BI 655130 [92]. Once new data from current clinical trials are published, we may also have a better understanding of the impact of the new treatments on associated comorbidities: for example, current biologics may also treat some cases of psoriatic arthritis (IL-17 inhibition) or inflammatory bowel disease (TNF/IL-23 inhibition). It is also expected that new guidelines for GPP management in North America and Europe will be developed and published within the next several years. Increased understanding of GPP pathogenesis will continue to improve our comprehension of this condition and the availability of newly developed targeted therapies will, hopefully, improve the treatment and quality of life of affected individuals.

Article highlights

• GPP is a rare and severe multisystem disease, characterized by the sudden and widespread eruption of superficial sterile pustules – that may or may not be preceded by a history of plaque psoriasis – and potentially severe systemic complications may occur.

• There is no standard treatment for GPP – guidance often follows that for plaque psoriasis treatment – and no therapeutic agents have been approved for GPP in the United States or Europe to date.

• Ideal therapeutic agents in GPP would have a rapid onset of action, a rapid time to achieve disease clearance, the ability to prevent acute flares, and a favorable safety profile; such therapies should be readily accessible via approval or listing on formularies.

• A scoring system to establish GPP disease burden could help with treatment access issues; objective outcome measures that are tailored to assess the clinical features of GPP are also required, and could facilitate comparisons between therapies.

• Lack of inhibition of IL-36R (i.e., exaggerated IL-36 signaling), associated with a loss-of-function mutation in IL36RN that leads to functional impairment of the antagonist IL-36Ra, appears to be a key mechanism in the pathogenesis of GPP.

• The IL-36 axis is associated with preferential expression of IL-36 cytokines, keratinocyte expression of neutrophil chemokines, and induction of inflammatory keratinocyte responses.

• New GPP therapies using biologic agents that target pro-inflammatory pathways, including the IL-36 axis, are in various stages of clinical development.

Declaration of interest

M.J. Gooderham has been a speaker, advisory board member, and/or clinical investigator for AbbVie, Amgen, Akros, Arcutis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermira, Galderma, GSK, Janssen, Kyowa Kirin, Leo Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, UCB, and Valeant/Bausch Health.

A.S. Van Voorhees has been a consultant for AbbVie, Amgen, Aqua, AstraZeneca, Celgene, Corrona, Dermira, Janssen, Leo, Novartis, and Pfizer; received a research grant from AbbVie; and has other relationship with Merck.

M.G. Lebwohl is an employee of Mount Sinai, which receives research funds from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Incyte, Janssen/Johnson & Johnson, Kadmon, Leo Pharmaceuticals, Medimmune/AstraZeneca, Novartis, Pfizer, SCIderm, UCB, Ortho Dermatologics, and Vidac; M.G. Lebwohl is also a consultant for Allergan, Aqua, Arcutis, Boehringer Ingelheim, Bristol-Myers Squibb, LEO Pharma, Menlo, Mitsubishi Pharma/NeuroDerm Ltd., Promius/Dr. Reddy, Regeneron, Theravance Biopharma, and Verrica.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have served as a speaker, advisory board member, and/or clinical investigator for AbbVie, Lilly, Almirall, Amgen, Celgene, Dermira, Galderma, Janssen, Leo Pharma, Novartis, Pfizer, Sanofi, UCB. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Acknowledgments

Medical writing assistance, supported financially by BIPI, was provided by Debra Brocksmith, MB ChB, PhD, of Elevate Scientific Solutions during the preparation of this manuscript. BIPI was given the opportunity to check the data used in this manuscript for factual accuracy only.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This paper was funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The authors received no direct compensation related to the development of the manuscript.