Current management of generalized pustular psoriasis

Generalized pustular psoriasis (GPP) is a rare subset of psoriasis involving episodes of sterile pustules accompanied by inflammation and, often, systemic involvement. The inflammatory nature of GPP has potential for severe multisystem complications including high‐output cardiac failure, infections, digestive system issues, and disfiguring or lethal acute flare episodes. The disease tends to have higher prevalence in females and Asians. The IL‐1/IL‐36 inflammatory pathway is a critical facet of GPP's pathology. Genetic mutations that are associated with GPP include modifications of Interleukin 36 Receptor Antagonist (IL36RN), Caspase Recruitment Domain Family Member 14 (CARD14), Adaptor Related Protein Complex 1 Subunit Sigma 3 (AP1S3), Myeloperoxidase (MPO) and Serpin Peptidase Inhibitor Clade A Member 3 (SERPINA3) genes. Treatment guidelines for GPP are not well‐entrenched. Currently, only one GPP‐specific treatment, the interleukin‐36 receptor antagonist (IL‐36Ra) spesolimab, has been approved for use in the United States. Additional anti‐IL‐36 pathway therapies are currently being developed. Other treatment options include other biologic therapies such as IL‐17 inhibitors, IL‐23 inhibitors and TNFα inhibitors. Non‐biologic therapeutic options include retinoids, cyclosporine and methotrexate. Treatment options differ throughout the world; most countries utilize retinoids, cyclosporine and methotrexate as first‐line non‐biologic options. China and United Kingdom have no GPP‐specific biologic therapies approved for use, while several biologic therapies are approved for use in Japan. This review aims to serve as an update on the current global management of GPP while also including relevant aspects of disease pathogenesis, diagnosis, clinical presentation, histopathology, aetiology and epidemiology.

grouped sterile pustules typically on an erythematous base. Pustules may coalesce into pus "lakes" during cutaneous flares, which are painful and can be disfiguring. 7 GPP is a potentially life-threatening disease that may present with repeated acute flares involving systemic inflammation or as a chronic disease with intermittent flares. 8 Although potentially life-threatening, management of GPP has been limited due to its rarity and lack of well-entrenched treatment guidelines. 9 Recent advancements in the pathogenesis of GPP have led to novel treatment options such as spesolimab, a FDA-approved GPPspecific treatment. 10 This review aims to provide an update on the management and pathogenesis of GPP while also briefly investigating the relevant epidemiology, aetiology and histopathology of the disease. Factors to consider when ruling out differentials will also be explained to facilitate timely and accurate diagnoses.

| EPIDEMI OLOGY
Global GPP prevalence estimates have been a challenge to document due to the heterogeneous prevalence of the disease across different locations and patient populations. Although there is no definitive consensus on the global prevalence of GPP, a recent study utilized different geographical GPP prevalence results to estimate a global prevalence range of 1.76 to 124 affected GPP patients per million people (0.0001% of the global population). 11 GPP prevalence varies across different countries. In France, a retrospective survey of 121 dermatological wards estimated a prevalence of 1.76 affected GPP patients per million people. 12 A different study done in Brazil looked at hospital databases from 2018 to 2020 and estimated the prevalence to be between 7 and 9 patients per million. 13 A third study used data from a Korean health insurance database between 2011 and 2015 and estimated a prevalence between 88 and 124 patients per million people a year. 11 Females tend to be more likely to present with GPP than males.
One study from France estimated that females were 1.3 times more likely to have GPP than men. 12 A similar study investigated in Brazil showed that 53% of GPP patients across public hospitals in Brazil were female. 13 Another study done in Malaysia assessed GPP patients from 1989 to 2011 and found that GPP was twice as prevalent in females than males. 5 In Thailand, GPP patients from 2005 to 2021 were found to be 76.7% female. 14 Prevalence also differs based on ethnicity and is estimated to be higher in Asian populations compared to Caucasian populations.
Studies have estimated 7.46 GPP patients per million in Japan while only 1.76 GPP patients per million in France. 12,15 Although GPP can occur at any age, the mean age of onset is estimated to be in the fourth or early fifth decade of life. 5,12 Common comorbidities of GPP include obesity, hypertension, hyperlipidaemia, diabetes mellitus and prior psoriasis. 4,5 The global mortality rate data for GPP are relatively limited and confined to geographically localized studies. It is estimated to be between 2% and 7% worldwide, but this rate differs across countries. Malaysian, Korean and Japanese studies found mortality rates of 6.86%, 6.06% and 4.2%, respectively. 5,16,17 A study in France reported a serious complication rate of 17% and a mortality rate of 2%. 12 The average hospital stay during a flare also differs in different regions. A Malaysian study reported a mean stay of 10.3 days with a range of 3 to 44 days. 5 A study conducted in France from 2012 to 2015 that included 569 inpatients reported a mean hospital stay was 11.5 days with 25% of patients being admitted to the ICU. 18

| AE TIOLOGY
A large spectrum of genetic mutations have been implicated in GPP.
Mutations in the IL36RN gene lead to a deficiency in the interleukin-36 receptor antagonist (IL-36Ra) and have been thought to be a primary driver of GPP. 19 Homozygous mutations of IL36RN were seen to have more severe consequences than heterozygous mutations and are inherited in an autosomal recessive manner. 20 Mutations in the CARD14 gene are also implicated in GPP progression. These mutations are inherited in an autosomal dominant manner and can upregulate the caspase recruitment domain family member 14 protein (CARD14), which is specifically expressed in the skin and results in the activation of nuclear factor kappa B (NF-κB) signalling. 19 Adaptor Related Protein Complex 1 Subunit Sigma 3 (AP1S3) mutations are also implicated in GPP and result in the destabilization of the adaptor protein complex 1 (AP-1). 21 Autosomal recessive partial or complete loss-of-function mutations in the MPO gene that lead to a deficiency in the neutrophil enzyme myeloperoxidase (MPO) are also associated with GPP. 8 There are differences in the prevalence of the IL36RN mutation in GPP patients based on ethnic group and the presence of concurrent PV. One study analysed data from European, North African and Asian patients and found that 23.7% of this multi-ethnic patient cohort carried IL36RN mutant alleles. 19 A different study investigating Han Chinese GPP patients found that 60.47% of patients had an IL36RN mutation, indicating a higher prevalence in this population. 22 The aetiology of GPP without PV likely differs from that of GPP in conjunction with PV. Approximately 53%-65% of patients with GPP have a prior PV diagnosis. 4,5 One study found that 82% of Japanese patients with GPP alone had IL36RN mutations while only 10% of Japanese patients with both GPP and PV had the same mutation. 23 CARD14, AP1S3 and MPO mutations have a lower association with GPP, with a prevalence of at most 5.9%, 10.8% and 12.8%, respectively. 8,24 Due to the genetic basis of GPP, there is often a family history of psoriasis and GPP for patients with GPP. In fact, a study conducted in Malaysia on 102 GPP patients found that 29% of the patients had a family history of psoriasis and 11% of the patients had a family history of GPP. 5 Drug-related triggers are common, including steroid withdrawal, antimalarials, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors and lithium. 25,26 Pregnancy, menstruation, stress, upper respiratory tract infections and bacterial infections may also trigger GPP. 5 A recent study linked COVID-19 infection to subsequent   diagnosis or exacerbation of GPP, with an average time of 19 days between a COVID-19 infection and a pustule eruption. 27

| CLINIC AL PRE S ENTATION
Clinically, GPP is characterized by recurring, widespread and painful flares of sterile pustules 2-4 mm in diameter on inflamed and erythematous skin. 28 These pustules are grouped together, can number up to the hundreds and can become confluent to form "lakes of pus." When pustules dry up, they peel off and reveal either a red or normal skin underneath. The severity and frequency of flares vary between patients and between different flares in the same patient. Patients may have multiple flares per year or one flare every few years and these episodes usually last from 2 to 5 weeks, but may continue for over 3 months. 20 GPP results in the protective functions of the skin being significantly diminished or lost, which can manifest in several ways.
Patients lose heat through the skin and generally lose temperature control ability, becoming febrile or hypothermic. Because sepsis is the most common cause of death among patients with GPP, fever workup is important. Fluids are also lost through the skin, causing hypotension and in some cases shock or acute renal failure. Other common symptoms include hypoalbuminemia resulting from protein loss, anaemia resulting from iron loss, electrolyte imbalance and hypocalcemia resulting from electrolyte loss, arthritis and leukocytosis. 20 Additionally, mucosal abnormalities can occur and lead to cheilitis, genital lesions or geographic tongues. Serious complications may lead to high-output cardiac failure and bilateral leg oedema. 29 There are several subtypes of GPP, including generalized and localized types. The von Zumbusch type is generalized and is the most severe form of GPP, leading to extreme symptoms. 30 Another generalized form of GPP is annular pustular psoriasis (APP), which is subacute and has mild systemic symptoms. It is characterized by annular lesions with pustules, erythema, scaling and few laboratory abnormalities. However, there is debate as to whether or not APP is a separate disease from GPP. 29 Another condition misclassified as a form of GPP is acute generalized exanthematous pustulosis (AGEP), a generalized pustular eruption occurring within 24 h of ingestion of a causative drug, most commonly antibiotics. 20 It is characterized by a sudden flare of sterile pustules and is usually short-lived, resolving within a few weeks. There is no relation to psoriasis and AGEP usually occurs in patients who do not have a history of psoriasis.
Juvenile pustular psoriasis and pustular psoriasis of pregnancy are other generalized forms of GPP that affect the paediatric and pregnant populations, respectively. 31 Localized forms are painful, but not life-threatening. Palmoplantar pustular psoriasis, which affects the palms and soles, and acrodermatitis continua of Hallopeau (ACH), which affects the distal digits, are both types of localized pustular psoriasis. 31 GPP may occur in patients without a history of psoriasis and can present with or without plaque psoriasis. Laboratory results that may be indicative of a GPP flare include elevated C-reactive protein (CRP) levels, elevated erythrocyte sedimentation rate (ESR), hypocalcemia, hypoalbuminemia, neutrophilia and abnormal liver function tests. 20,29 During a GPP flare, high fever has been reported in about 24%-96% of patients with neutrophiliadominated leukocytosis being reported in about 30%-70% of patients. 20 Iron deficiency anaemia is common. The type and severity of both cutaneous and extracutaneous symptoms vary widely both between and within patients, making GPP an unpredictable disease.

| HIS TOPATHOLOGY
The histopathology of GPP involves the formation of spongiform pustules of Kogoj in the subcorneal portion of the epidermis. 6 These form as a result of neutrophil accumulation beneath the stratum corneum into necrotic epidermis in a sponge-like pattern. 33,34 Acute GPP shows pustules concentrated deeper in the epidermis than in chronic GPP. 35 Older GPP pustules may lack spongiform changes due to epidermal healing over time. 36 Other GPP characteristics include a reduction in the granular layer causing abnormal maturation of keratinocytes and nuclei to be retained in cells at the stratum corneum. 34,37 Psoriasiform hyperplasia may also be present in those with GPP. 38

| Acute generalized exanthematous pustulosis
GPP is often mistaken for acute generalized exanthematous pustulosis (AGEP), an acute onset pustular drug reaction. AGEP is generally less severe than acute GPP flares as the skin does not lose as much of its functionality. 35 AGEP can be treated in 1 to 2 weeks by withholding the causative medication. Abrupt onset, short duration, non-recurrence, and no psoriasis or arthritis comorbidity are indicators of AGEP over GPP. Furthermore, if symptoms begin shortly after using specific drugs and heal at the cessation of drug use, an AGEP diagnosis is favoured. 35 There are also histological differences between GPP and AGEP. GPP shows subcorneal pustules of Kogoj with or without psoriasiform changes while AGEP shows intraepidermal or subcorneal pustules with neutrophils, eosinophils, necrotic keratinocytes and no psoriasiform changes. 31,35,39 In AGEP, subcorneal pustules can be found touching intraepidermal pustules and are spongiform, which is less prominent than in GPP. 35 Although AGEP typically has non-follicular pustules, the presence of follicular pustules does not exclude AGEP. 35

| Subcorneal pustular dermatosis
Subcorneal pustular dermatosis (SPD) is another prominent differential diagnosis for GPP. GPP and SPD present in a similar clinical and histologic manner, and the histology of GPP and SPD can be indistinguishable. 36 Both GPP and SPD are most common in adults over 40 years old and have similar recurring episodes of pustules. 40,41 Inflammation resolves following treatment in several days in both conditions as well. 36 However, several clinical symptoms have been used to differentiate the diseases. SPD pustules arise as halfpustular, half-vesicular blisters whereas GPP pustules are commonly purely pinpoint. 36 Histologic differences that are typically exclusive to GPP include psoriasiform changes, parakeratosis, elongated rete ridges, spongiform pustules of Kogoj and acantholysis. 36

| Pustular drug eruption
Pustular drug eruption is another disease with a similar presentation to GPP and is characterized by skin pustules and fever as a result of a negative drug interaction. However, unlike GPP, in pustular drug eruption, there is no personal or family history of psoriasis.
Furthermore, there is a spontaneous resolution when the causative drug is stopped. Histological features unique to each disease are the presence of eosinophils in the inflammatory infiltrate in pustular drug eruption and the presence of psoriasiform changes and spongiform pustules of Kogoj in GPP. 42 Other differential diagnoses for GPP include folliculitis, miliaria, Candida infection and other localized forms of PP. [43][44][45] 8 | PATHOG ENE S IS

| IL-36RN mutation
The pathogenesis of GPP still remains under investigation, but many familial GPP cases and some sporadic GPP cases are linked to a loss-of-function L27P substitution in the IL36RN gene

| CARD14 variant
CARD14 gain-of-function variants have also been identified in GPP patients. 33 CARD14 encodes a keratinocyte adaptor protein. 33 Normally, CARD14 is localized primarily in the basal and suprabasal epidermal layers; in diseased skin, expression of CARD14 is reduced in the basal layer and upregulated in the suprabasal epidermal layers. 57 CARD14 activates NF-kB signalling, upregulating genes in keratinocytes including chemokine ligand 20 (CCL20) and interleukin 8 (IL-8), initiating inflammatory recruitment and leading to epidermal inflammation. 57 However, CARD14 variants were found only in a small number of cases and were not as prevalent as IL36RN variants in GPP patients. 40 The CARD14 mutations provide further evidence that GPP with PV has a distinct aetiology from GPP alone. In a direct sequencing analysis of the coding region of CARD14 across different phenotypes, it was found that none of the 11 GPP patients without PV had CARD14 mutations, while 4 of the 19 patients with GPP and PV had CARD14 variants. All four of these patients were heterozygous for the same CARD14 gene variant (c.526G>C). 58 F I G U R E 1 GPP pathogenesis. GPP pathogenesis primarily constitutes a large IL-36-dominated keratinocyte cytokine storm and epidermal neutrophil aggregation. [46][47][48] Epidermal neutrophil recruitment leads to pustular skin symptoms, and this recruitment is sustained and long-lived due to an MPO deficiency. 49 These keratinocyte cytokines stimulate various inflammatory mediators such as Th17 cells, dendritic cells and neutrophils. 46 Th17 stimulation causes a release of IL-17A, which increases IL-36 levels. 46 Dendritic cells release TNFα and IL-23, which further stimulate Th17 and increase IL-36 levels. 46 An MPO deficiency enhances the activity of neutrophil-derived proteases, which continue to activate IL-36. 49 An IL-36RN LOF mutation is the primary mutation implicated in GPP that produces dysfunctional IL-36Ra, which normally functions to inhibit IL-36R, stop cytokine production and prevent inflammation. 49 With no inhibitory protein for IL-36R, large levels of IL-36 constitutively activate IL-36R, which further activates NF-κB and MAPK for more release of pro-inflammatory cytokines in a constant positive loop. 50 Various other mutations add to this increase in IL-36. An AP1S3 LOF mutation causes P62 buildup leading to NF-κB activation and further IL-36 release. 49 A CARD14 GOF mutation also οveractivates NF-κΒ for additional cytokine release. A rare SERPINA3 deletion (not shown in figure) can cause hyperactivation of IL-36 precursors and further increase IL-36 levels. 49

| AP1S3 mutation
AP1S3 loss-of-function mutations are also implicated in GPP pathogenesis. These genetic abnormalities impair the AP-1 complex subunit σ1C, which is involved in the assembly of clathrin-coated vesicles for transport. 21 These mutations make the AP-1 complex less stable and thus inhibit vesicle delivery between the trans-Golgi network and endosomes. 21,59 This disrupts endosomal translocation of Toll-Like-Receptor 3 (TLR-3) and can inhibit downstream signalling in skin keratinocytes. 21 Cells with mutations in AP1S3 have decreased autophagosome formation in keratinocytes, leading to p62 buildup. 60 Large quantities of p62 cause increased NFκB signalling, leading to the overexpression of IL-36α and subsequent overactivation of the IL-36 pathway. 21,46 Like CARD14 variants, AP1S3 variants were found in fewer GPP cases than IL36RN. A study examining genetic differences in psoriasis patients found that 4 out of the 251 GPP patients tested had

| MPO deficiency
Deficiency in the MPO gene encoding myeloperoxidase has only recently been associated with GPP. 49 Myeloperoxidase is a haemcontaining peroxidase released by neutrophil granulocytes that catalyses the formation of reactive oxygen species (ROS) including the peroxidation of chloride ions to form hypochlorous acid (HClO). 49,61 The antimicrobial activity of the MPO/HClO system is an integral component of the innate immune response. 62

| SERPINA3 deletion
A rare, heterozygous loss-of-function deletion in the SERPINA3 gene has been implicated in the progression of GPP. Sanger sequencing determined that the same heterozygous SERPINA3 deletion was found in two different GPP patients. Correlation tests found that the rare genetic deletion was significantly associated with GPP prevalence. 64  of control patients achieved a GPPGA total score of 0 or 1, respectively. Additionally, 54% of patients receiving spesolimab compared to 18% of the placebo cohort had a GPPGA pustulation subscore of zero, indicating no visible pustules, by the end of 1 week. 82 It was also found that groups receiving spesolimab had a higher incidence of infection. 82 However, these infections were neither opportunistic nor severe.  47,48,[68][69][70][71][72][73] The only GPP-specific treatment that is currently FDA-approved in the United States is spesolimab, an anti-IL-36R antibody. 74 Other treatments include additional inhibitors of the IL-36 pathway, IL-17 inhibitors, IL-23 inhibitors, TNFα inhibitors, retinoids, calcineurin inhibitors, anti-folate therapy and PDE4 inhibitors. 47 Adapted from "Risk Factors of Dementia", by BioRe nder.com (2022). Retrieved from https://app.biore nder.com/biore nder-templ ates. GPP, Generalized pustular psoriasis; IL, Interleukin; TNF, Tumor necrosis factor; PDE, Phosphodiesterase. ing IL-36γ's receptor-binding capability. 84 Phenotyping of individuals who lack the IL-36R-encoding gene revealed that they are not severely immunocompromised, further proving that the IL-36 pathway is a favourable therapeutic target with minimal side effects. 85 Interleukin-1 receptor accessory protein (IL-1RAcP) antibodies are another potential future management option for GPP patients.
When IL-36R binds with an agonist, it dimerizes with IL-1RAcP and activates the downstream Myd88 pathway. 86 The Myd88 pathway then can activate various pro-inflammatory transcription factors such as NF-κB, AP-1 and STAT3. 79 Inhibiting IL-1RAcP's ability to dimerize with IL-36R could prevent the IL-36 pathway overactivation and the following inflammation cascade. However, additional studies need to be conducted to determine the long-term safety and efficacy of IL-1RAcP treatments for use in GPP because IL-1RacP is expressed in many different cell types and inhibition could lead to various toxicities. 79

| TNFα inhibitors
TNFα is associated with increased production of IL-36R agonists, which stimulate the IL-36 pathway that induces more TNFα production in a continuous inflammatory loop. TNFα inhibitors indirectly suppress the expression of IL-36γ, which leads to reduced activation of the pro-inflammatory IL-36 pathway. 87,88 Adalimumab, infliximab and certolizumab pegol are TNFα inhibitors approved for use in Japan. 47 It should be noted that because GPP can be deadly and until recently specific treatments that work quickly in most patients were not available, endpoints in trials for GPP often used any improvement at all as a clinical endpoint.
In Japan, a case study examining a woman with GPP and psoriatic arthritis (PA) identified that after the administration of a single 3 mg/ kg infliximab injection, the patient's pustular lesions cleared within 48 h. After a second 3 mg/kg injection, the patient's joint mobility was notably improved. The patient received a 3 mg/kg infliximab injection every 8 weeks for long-term management and over a 12month period, no relapse of GPP or PA symptoms was noted. 89 F I G U R E 3 GPP-specific Spesolimab treatment pathway. Epidermal IL-36 pathway in healthy, GPP, and spesolimab treatment. 48,75,76 IL-36 is mainly expressed in epidermal, bronchial, intestinal epithelial and various immune cells. 46 The IL-36 pathway regulates the balance of pro-inflammatory and anti-inflammatory cytokine production at these tissue sites. 46 (A) IL-36Ra is an IL-36R antagonist and immune regulator. 50 The Asp148 residue in the β11/12 loop of IL-36Ra prevents heterodimerization of IL-36R and the accessory protein IL-1RAcP and attachment of IL-36 agonists through steric hindrance, blocking an inflammatory response through the pathway. 77 (B) Many GPP patients have dysfunctional IL-36Ra with limited binding capability and reduced stability. 78 This leaves IL-36R open to bind with agonists including IL-36α, IL-36β and IL-36γ. 46,78 This causes uncontrolled activation of the IL-36 pro-inflammatory pathway, which has been implicated in the pathogenesis of GPP. 46 (C) Spesolimab is an antagonistic anti-IL-36 receptor antibody treatment that seeks out and binds to IL-36R. 79 This binding prevents IL-36R agonists from binding to IL-36R and activating the inflammatory IL-36 pathway, leading to skin and pustular clearance. 79 Adapted from "Blank Comparison Pathway (Linear)", by BioRe nder.com (2022). Retrieved from https://app.biore nder.com/biore nder-templ ates. GPP, Generalized pustular psoriasis; IL, Interleukin; IL-1RAcP, Interleukin-1 receptor accessory protein.
While effective, TNFα inhibitors do display adverse effects. In a Turkish study examining 156 GPP patients, TNFα inhibitors were the only biologic GPP treatment that triggered paradoxical GPP. 90 An estimated 0.6%-5.3% of patients treated with TNFα inhibitors develop paradoxical GPP, and the most common drug associated with paradoxical GPP was infliximab. 91,92

| IL-17 inhibitors
IL-17A and IL-17RA inhibitors include the medications secukinumab, ixekizumab and brodalumab. All three of these biologics are approved for use with GPP patients in Japan, and brodalumab is also approved for use in Thailand and Taiwan. 47,93 A clinical trial investigating the efficacy of brodalumab found that out of 12 GPP patients treated with brodalumab, 10 (83.3%) patients had significant remission of GPP symptoms after 12 weeks.
After one year, 11 of 12 patients (91.6%) achieved improvement or remission of GPP symptoms. 93 There is no meaningful causative relationship between the use of brodalumab and suicidal ideation. 94 In fact, there has only been one suicide documented worldwide after nearly half a decade of brodalumab's use. 95,96 As a preventative measure in the United States, brodalumab prescriptions can only be administered going through the SILIQ risk evaluation and mitigation strategy program, a program designed to manage the risk of suicidal thoughts and actions. 94 Brodalumab should not be prescribed to individuals with a history of suicidal thoughts. 94 Secukinumab and ixekizumab have also been established as effective treatments for GPP. Secukinumab was found to be effective in a phase 3 trial involving 12 patients with GPP. 97

| Steroids
Other medications that have been used to manage GPP include systemic steroids. Although systemic corticosteroids can quickly alleviate pustular symptoms, significant side effects limit their clinical effectiveness. Ryan and Baker determined that the management of GPP with systemic corticosteroids was associated with increased deaths and decreased lasting remission. 101 A retroactive study from Japan showed that hospitalized patients treated with only systemic corticosteroids had an above-average mortality rate. 17 Additionally, withdrawal of systemic corticosteroids following treatment frequently brought about increasingly severe GPP flares 101 that are resistant to increasingly high steroid doses.
The topical steroid betamethasone dipropionate can also initiate GPP flares. Using steroid cream over large skin areas for an extended amount of time for the management of PV or maintenance of GPP is not recommended due to the risk of inducing acute GPP if betamethasone dipropionate is absorbed through compromised skin. 102 Symptomatic treatment can also be employed to alleviate symptoms associated with the disease. Triamcinolone acetonide ointment and full-body wet wraps are used to reduce crusting and scaling and minimize discomfort, and whirlpool treatments clean the skin. 103 However, these treatments do not work quickly enough to suppress symptoms of an active outbreak.

| Retinoids
Retinoids were found to inhibit the differentiation of Th17 cells while also inducing T regulatory cell expression, promoting an antiinflammatory response. 104 Retinoids may also limit the production of TNFα, IL-1 and IL-6. 47,105 Acitretin can be effective in addressing GPP, but when given as a maintenance dosage (10-30 mg/day), patients reported mild recurrence of symptoms at follow-up. 106 Acitretin is teratogenic, which is also a concern when prescribing to individuals of child-bearing age, and its effects can last for years after treatment. 107 It is recommended that patients wait at least three years after ceasing acitretin treatment to become pregnant due to the conversion of acitretin to etretinate when alcohol is consumed. 108 In addition, capillary leak syndrome can be a concern when prescribing acitretin; if this issue arises, retinoic acid treatment should cease immediately. 109 Corticosteroid therapy may alleviate symptoms, and acitretin treatment should be discontinued permanently in patients who exhibit capillary leak syndrome. 110,111 As an alternative to acitretin, isotretinoin is also used in the management of GPP. Isotretinoin has a shorter teratogenic period than acitretin; it is recommended that patients wait at least one month after ceasing isotretinoin treatment to become pregnant. 112 A notable concern when prescribing isotretinoin is immediate availability; all isotretinoin users must register in the iPLEDGE database and individuals of child-bearing age must pledge to abstinence or use two simultaneous methods of contraception, making it difficult to maintain long-term treatment adherence. 107,113 When successful, isotretinoin is faster-acting than other GPP medications. 47

| Cyclosporine
Cyclosporine is a calcineurin inhibitor that sequentially inhibits nuclear factor of T cells (NFAT), a transcription factor responsible for inflammatory cytokine production. This modulates immune responses by decreasing the production of cytokines that activate pro-inflammatory T cells, 114 preventing these T cells from further activating the IL-36 pathway. Cyclosporine was found to be effective in addressing acute GPP episodes for some patients. In one retroactive study, 102 GPP patients were treated with various potential GPP treatments. Eight patients with acute GPP episodes responded to cyclosporine; this included 2 patients with pustular psoriasis of pregnancy for whom cyclosporine treatment was successful in controlling an outbreak. 5 The use of cyclosporine in the management of chronic GPP is less effective, with recurring flares being only partially controlled and the potential for hypertension to develop with extended use. 5

| Methotrexate
Folic acid antagonists such as methotrexate may also be used to treat GPP. Treatment of GPP with methotrexate was found to be less effective in patients that had received prior steroid treatment. 101 Many patients with GPP have associated renal disease, hepatic disease or a diabetes mellitus comorbidity; methotrexate should be used with caution in these patients. 115 Furthermore, patients undergoing treatment with methotrexate, especially patients over age 70, should be monitored for hematologic toxicity. 116 Methotrexate is a particularly common treatment option for paediatric patients with GPP; although hepatic function while on methotrexate is a pressing concern in adult cases, no cases of hepatic fibrosis have been reported in children using methotrexate to manage psoriasis.
Methotrexate is teratogenic and should not be used to treat pregnant individuals with GPP. 117 Methotrexate is slower-acting than other GPP treatments. Due to its slow onset of action, attaining an adequate dose may take several weeks; it is recommended that the weekly dose begin between 5 mg and 15 mg and be increased by 2.5 mg each week as tolerated until symptoms are manageable. 105 Paediatric patients should receive no more than 25 mg of methotrexate weekly. 118 Methotrexate therapy may be more helpful for the management of chronic GPP than acute GPP due to its slow onset of action. In circumstances where other medications are not tolerated, methotrexate may be valuable for the treatment of acute GPP. Treatment via methotrexate is particularly applicable for patients with GPP who have been treated with acitretin and had minimal improvement or adverse side effects.

| Apremilast
Apremilast is a phosphodiesterase-4 (PDE4) inhibitor. PDE4 inhibition has been shown to raise cyclic-AMP (cAMP) levels and decrease the secretion of IL-23, 119,120 which may lead to decreased epidermal inflammation. In a case report studying an individual with PV, GPP and multiple comorbidities, apremilast was effective in achieving near-clearance of both PV and GPP after 2 to 3 weeks of treatment. 47,121 The patient began with a 10 mg dose, which was increased by 10 mg each day until a maximum dose of 60 mg/day (30 mg twice/day) was established. The patient's PV and GPP were completely cleared after 6 weeks of treatment; on the 60 mg/day maintenance dose, the patient had no recurrence of PV or GPP for at least 9 months. 121 Another study combined apremilast and infliximab to maintain GPP outbreak remission in a patient with GPP, ACH and multiple comorbidities including diabetes and neuropathy. The patient was treated with apremilast and infliximab and had minimal GPP relapse for several months. 122 Apremilast may be useful as a systemic therapy for individuals who are unable to tolerate other medications due to side effects or comorbidities. Furthermore, this medication is not contraindicated in patients with infections and can be used in the management of acute and chronic GPP. 121

| Global management and treatment options
Substantial variations in the management of GPP exist throughout the world. Biologic therapies have been approved for use in Japan, Taiwan, Thailand and the United States. 9 In Brazil, Egypt, Germany, China and Japan, patients are more likely to report directly to a dermatologist, possibly making timely and accurate diagnosis more likely. 9 Furthermore, drug availability for treatment varies largely worldwide. Countries such as the United States and Russia have better drug availability than other countries including the Philippines and Indonesia. 123,124 Better drug availability allows these countries to provide more immediate and personalized treatment options while countries with less drug availability resort to alternative nonspecific therapies or supportive care available for use. In many countries, conventional PV medications and biologics are the first-line treatments for GPP. 125 Retinoids or cyclosporine are the first-line treatments for the management of GPP in Japan. 126 With the availability of spesolimab, it is likely that prescribing patterns will take into account this reliably and rapidly effective treatment. Several biologic agents have been approved for use in treating GPP in Japan when a refractory response to non-biologic therapies is observed. 124 IL-17 inhibitors including secukinumab, ixekizumab and brodalumab are licensed for the treatment of PV and GPP in Japan. 124 TNFα inhibitors and IL-23 inhibitors are also approved for the treatment of severe GPP that is unresponsive to traditional first-line therapies. 126 In Europe, no biologic agents are approved for the treatment of GPP, so systemic non-biologic agents and biologics used for PV are typically used for treatment and management of GPP. 124 PV biologics are, however, less effective in treating GPP than in PV. Common non-biologic systemic agents used for the treatment and management of GPP in Europe include acitretin, cyclosporine A and methotrexate. Corticosteroids and acitretin are the only systemic drugs that are licensed in Germany to treat GPP. 115 As mentioned above, the availability of spesolimab will likely impact treatment of GPP in Europe.
Biologic agents specific to GPP are also not approved in China. In addition to systemic therapies, topical treatments are recommended with the aim of maintaining skin hygiene and integrity. Topical calamine is used to minimize pustules, decrease irritation and maintain skin hygiene during outbreaks. 125 Herbal topical and systemic therapies are often used on their own or in combination with Western treatments. 125 It is vital that additional medications that work quickly to alleviate the symptoms of active GPP outbreaks are developed, tested and approved for use. Methods to predict GPP outbreaks should also be elucidated and would allow for more effective lifelong management of the condition.

| MA JOR OPEN QUE S TI ON S
Numerous gaps of knowledge exist in the understanding of GPP.
One notable concern when managing patients with GPP is predicting and recognizing acute flares as soon as possible. Rapid recognition of acute illness can minimize the duration and severity of patient discomfort and reduce the risk of complications arising from disease pathology. 31 19,22 As such, the most effective treatments available for GPP may vary between different ethnic groups with disparate GPP gene mutations. However, recruitment of a sufficient number of patients by ethnicity may be a challenge due to the rarity of the condition. 31,82 Retroactive studies could be employed to determine relationships between ethnicity and the efficacy of a particular medication in order to increase cohort sizes.
The approval of spesolimab in the United States has brought about a need for updated guidelines for the treatment and management of GPP. 31,74 Experiments that provide more robust data comparing the side effects and efficacy of both biologic and non-biologic medications for GPP are necessary to inform novel GPP treatment guidelines.
Disparities in GPP treatment options exist for women of childbearing age due to the teratogenicity of several medications. 47 Currently, individuals of child-bearing age who manage chronic GPP with retinoids or folic acid antagonists must either abstain from becoming pregnant or discontinue therapy prior to conceiving. Nonteratogenic therapies should be investigated and assessed for use in pregnant individuals. Prompt development and approval of additional biologic therapies for the treatment and management of GPP may help to address this issue.

| CON CLUS I ON S AND PER S PEC TIVE S
GPP is a severe inflammatory condition that can be life-threatening. 105 During flares, skin is compromised such that patients are at significant risk of hypothermia and infection, particularly in a hospital environment. Additional potentially debilitating complications include the potential for systemic inflammation and high-output cardiac failure. 20 Acute GPP episodes can be disfiguring and lethal, and it is critical to address flares as quickly as possible to minimize the risk of severe adverse events. 47 The main inflammatory pathway that has been implicated in GPP is the IL-36 pathway. 19 Various mutations of several genes, including IL36RN, CARD14, AP1S3, MPO and SERPINA3 alter the regulation of this inflammatory pathway, leading to uncontrolled inflammation and typical pustular symptoms. 49,64 Ideal treatments for GPP would rapidly address and clear cutaneous flares to minimize patient disfigurement and distress, and minimize the severity of GPP-related complications. 31 Maintenance therapies that can be used long-term (with minimal side effects) and are effective in preventing flares are also needed. 31 Although treatments are limited, the anti-IL-36 receptor antibody spesolimab recently became the first FDA-approved GPP-specific therapeutic agent in the United States for use in treating acute GPP flares. 74 The long-term efficacy of spesolimab in preventing GPP flares has yet to be elucidated, though clinical trials assessing the medication's effectiveness over a 48-week period are currently underway. 10 The availability of specific biologic therapy for the treatment of GPP may change GPP maintenance guidelines in the United States. 74 Depending on the presence and severity of side effects noted in the long-term clinical trial of spesolimab, this medication may be a suitable alternative for addressing chronic GPP to retinoids and folic acid antagonists, which have the drawbacks of teratogenicity and other side effects that can hinder long-term treatment. 47 Additional biologic options for the treatment of acute GPP and maintenance of chronic GPP should be investigated for use in the United States. 31 Updated guidelines for the management of GPP should be developed with biologic agents in mind. 31

AUTH O R CO NTR I B UTI O N S
N.K. and M.L. conceived of the paper. N.K., I.B. and S.K. wrote and edited the initial draft of the paper. N.K and I.B. created the figures. N.K. and M.L. edited and completed the final draft of the paper. All authors have approved the final paper.

ACK N OWLED G M ENTS
None.

FU N D I N G I N FO R M ATI O N
None.

CO N FLI C T O F I NTE R E S T S TATE M E NT
None.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

FI N A N CI A L D I SCLOS U R E S
None.