Received: 28 November 2022 | Revised: 6 January 2023 | Accepted: 8 February 2023

DOI: 10.1111/exd.14765

REVIEW ARTICLE

Current management of generalized pustular psoriasis

Nilesh Kodali1 | Isabella Blanchard1 | Sruthi Kunamneni1 | Mark G. Lebwohl2

1
Department of Education, Rutgers New
Jersey Medical School, Newark, New Abstract
Jersey, USA
Generalized pustular psoriasis (GPP) is a rare subset of psoriasis involving episodes
2
Dermatology, The Icahn School of
Medicine at Mount Sinai, New York City,
of sterile pustules accompanied by inflammation and, often, systemic involvement.
New York, USA The inflammatory nature of GPP has potential for severe multisystem complications

Correspondence
Mark G. Lebwohl, MD, FAAD Professor
& Chairman, Dermatology, Mount Sinai
–­The Icahn School of Medicine at Mount
Sinai, 5 East 98th St 5th Fl, New York, NY
10029, USA.
Email: lebwohl@aol.com
including high-­output cardiac failure, infections, digestive system issues, and disfig-
uring 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 thera-
pies 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 op-
tions 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 patho-
genesis, diagnosis, clinical presentation, histopathology, aetiology and epidemiology.

KEYWORDS
GPP, IL-­36, IL-­36Ra, IL-­36RN, psoriasis, Spesolimab, systemic inflammation, treatment, von
Zumbusch

1 | I NTRO D U C TI O N subtype of psoriasis, is associated with innate immune system over-

Psoriasis is a common chronic inflammatory skin condition with a
wide variety of clinical presentations. Psoriasis Vulgaris (PV), the
most common type of psoriasis, largely involves dysregulation of
the adaptive immune system.1 Pustular psoriasis (PP), a more rare
activity that leads to the characteristic erythematous, scaly skin in-
cluding pustules which can become confluent, forming lakes of pus. 2
PP can manifest in a variety of ways including localized pustules, as
in acropustulosis or palmoplantar pustulosis (PPP), or as intermittent
(and often systemic) inflammatory illness, as in generalized pustular

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.

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wileyonlinelibrary.com/journal/exd Experimental Dermatology. 2023;32:1204–1218.

KODALI et al.
psoriasis (GPP). PV makes up about 90% of all psoriasis cases,3 while
4,5
about 53%–­65% of individuals with GPP have concurrent PV.
Generalized pustular psoriasis (GPP) is a rare and life-­threatening
psoriasis subtype characterized by recurring fever, systemic flush-
ing and sterile pustules.6 Clinical presentations include hundreds of
grouped sterile pustules typically on an erythematous base. Pustules
may coalesce into pus “lakes” during cutaneous flares, which are
7
painful and can be disfiguring. GPP is a potentially life-­threatening
disease that may present with repeated acute flares involving sys-
temic 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 guide-
9
lines. Recent advancements in the pathogenesis of GPP have led to
novel treatment options such as spesolimab, a FDA-­approved GPP-­
10
specific treatment.
This review aims to provide an update on the management and
pathogenesis of GPP while also briefly investigating the relevant ep-
idemiology, aetiology and histopathology of the disease. Factors to
consider when ruling out differentials will also be explained to facil-
itate timely and accurate diagnoses.
2 | E PI D E M I O LO G Y
Global GPP prevalence estimates have been a challenge to docu-
ment 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 prev-
12
alence of 1.76 affected GPP patients per million people. A differ-
ent 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 be-
tween 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
12
likely to have GPP than men. 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 pa-
tients 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
|
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1205
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 coun-
tries. Malaysian, Korean and Japanese studies found mortality rates
of 6.86%, 6.06% and 4.2%, respectively.5,16,17 A study in France re-
ported 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
3 | A E TI O LO G Y
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 pri-
mary 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 mu-
tations are inherited in an autosomal dominant manner and can up-
regulate 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 associ-
ated with GPP.8
There are differences in the prevalence of the IL36RN mutation
in GPP patients based on ethnic group and the presence of concur-
rent 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 aeti-
ology 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
 |
1206
Drug-­related triggers are common, including steroid withdrawal,
antimalarials, beta-­blockers, angiotensin-­converting enzyme (ACE)
25,26
inhibitors and lithium. Pregnancy, menstruation, stress, upper
respiratory tract infections and bacterial infections may also trig-
ger 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
4 | C LI N I C A L PR E S E NTATI O N
Clinically, GPP is characterized by recurring, widespread and painful
flares of sterile pustules 2–­4 mm in diameter on inflamed and ery-
thematous 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 sig-
nificantly 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 pro-
tein loss, anaemia resulting from iron loss, electrolyte imbalance and
hypocalcemia resulting from electrolyte loss, arthritis and leukocy-
tosis. 20 Additionally, mucosal abnormalities can occur and lead to
cheilitis, genital lesions or geographic tongues. Serious complications
29
may lead to high-­output cardiac failure and bilateral leg oedema.
There are several subtypes of GPP, including generalized and
localized types. The von Zumbusch type is generalized and is the
30
most severe form of GPP, leading to extreme symptoms. 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
20
a causative drug, most commonly antibiotics. It is characterized by
a sudden flare of sterile pustules and is usually short-­lived, resolv-
ing 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 preg-
nant 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),
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KODALI et al.
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.
5 | D I AG N OS I S C R ITE R I A
Diagnostic criteria for GPP vary globally. The European Rare and
Severe Psoriasis Expert Network (ERASPEN) characterizes GPP as
primary, sterile and macroscopically visible epidermal pustules on
non-­acral skin. The guidelines state that GPP can occur with or with-
out systemic inflammation, with or without plaque psoriasis, and is
either relapsing (>1 episode) or persistent (>3 months).32 Japanese
criteria diagnose GPP based on 4 factors: (1) systemic symptoms
such as fever or fatigue; (2) systemic or extensive flush accompanied
by multiple sterile pustules; (3) neutrophilic subcorneal pustules his-
tologically characterized by Kogoj's spongiform pustules, and (4) the
recurrence of these clinical and histologic findings. A definitive di-
agnosis of GPP in Japan can be made in these patients who meet all
four criteria and GPP would be suspected in those who meet criteria
2 and 3.6
Laboratory results that may be indicative of a GPP flare include
elevated C-­reactive protein (CRP) levels, elevated erythrocyte sedi-
mentation 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 neutrophilia-­
dominated leukocytosis being reported in about 30%–­70% of pa-
tients. 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.
6 | H I S TO PATH O LO G Y
The histopathology of GPP involves the formation of spongiform pus-
tules 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
7 | D I FFE R E NTI A L D I AG N OS I S
7.1 | Acute generalized exanthematous pustulosis
GPP is often mistaken for acute generalized exanthematous pustu-
losis (AGEP), an acute onset pustular drug reaction. AGEP is gen-
erally less severe than acute GPP flares as the skin does not lose

KODALI et al.
as much of its functionality.35 AGEP can be treated in 1 to 2 weeks
by withholding the causative medication. Abrupt onset, short du-
ration, 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
35
use, an AGEP diagnosis is favoured. There are also histological dif-
ferences 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,
31,35,39
necrotic keratinocytes and no psoriasiform changes. 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
35
pustules does not exclude AGEP.
7.2 | Subcorneal pustular dermatosis
Subcorneal pustular dermatosis (SPD) is another prominent differen-
tial diagnosis for GPP. GPP and SPD present in a similar clinical and
histologic manner, and the histology of GPP and SPD can be indis-
36
tinguishable. 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 half-­
pustular, half-­vesicular blisters whereas GPP pustules are commonly
36
purely pinpoint. Histologic differences that are typically exclusive
to GPP include psoriasiform changes, parakeratosis, elongated rete
ridges, spongiform pustules of Kogoj and acantholysis.36
7.3 | Pustular drug eruption
Pustular drug eruption is another disease with a similar presenta-
tion to GPP and is characterized by skin pustules and fever as a re-
sult 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 spongi-
42
form pustules of Kogoj in GPP.
Other differential diagnoses for GPP include folliculitis, miliaria,
Candida infection and other localized forms of PP.43–­45
8 | PATH O G E N E S I S
8.1 | 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-­f unction L27P substitution in the IL36RN gene
|
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1207
(Figure 1). 6,51 This leads to a deficiency of interleukin-­36 receptor
antagonist (DITRA). These IL36RN gene variants are seen in about
24% of patients with GPP52 and are associated with an earlier
onset of disease.40 IL36RN mutations are not seen in individuals
that have both PPP and GPP, indicating that IL36RN mutations may
be responsible for a subtype of GPP without PPP. 53 The IL36RN
gene is primarily involved in regulating cutaneous innate immunity
by expressing the IL-­36R antagonist (IL-­36Ra), which suppresses
the IL-­36 receptor (IL-­36R) and its subsequent inflammatory cas-
cade. Genetic alterations in the IL36RN gene produce dysfunc-
tional IL-­36Ra that have decreased stability and faulty binding
to IL-­36R. Without an antagonizing modulation of IL-­36R and a
large induction of IL-­36R agonists (such as IL-­36α, IL-­36β and IL-­
36γ), 50,54–­56 the IL-­36R is unregulated and constantly activated. 53
This perpetuates a further downstream signalling cascade via NF-­
κB and mitogen-­a ctivated protein kinase (MAPK) that induces the
expression of pro-­inflammatory cytokines and chemokines such
as IL-­1, IL-­6 , IL-­36, IL-­8 , CXCL1 and CXCL20. 51,53 This massive cy-
tokine storm activates various inflammatory mediators (such as
dendritic cells) and attracts a large neutrophil infiltrate to the epi-
dermis. Activated dendritic cells secrete TNF and IL-­23, which can
activate nearby Th17 cells. Th17 cells, upon activation, produce
IL-­17A, a pro-­inflammatory cytokine that increases the synthesis
of more IL-­36R agonists such as IL-­36α, IL-­36β and IL-­36γ. IL-­17A
also activates the NF-­κ B pathway in fibroblasts, further increasing
the cytokine storm. The large neutrophil infiltrate that proceeds
causes the typical pustular rash seen in GPP.46 Without regulation,
this IL-­1/IL-­36 inflammatory pathway is fixed in a constant positive
feedback loop that leads to worsening cutaneous and systemic ef-
fects. Other IL36RN gene mutations have also been identified in
individuals with GPP, proving IL36RN as a major therapeutic target
for GPP. 53
8.2 | 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 lay-
ers.57 CARD14 activates NF-­kB signalling, upregulating genes in ke-
ratinocytes 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 pheno-
types, 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
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1208 KODALI et al.

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.46–­48 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 TNF-­α 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-­κ Β 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 Created with BioRe​nder.com.
GPP, Generalized pustular psoriasis; IL, Interleukin; MPO, Myeloperoxidase; TNF, Tumor necrosis factor; IL-­36Ra, Interleukin 36 receptor
antagonist; NF-­κB, Nuclear factor kappa B; MAPK, Mitogen-­activated protein kinases; LOF, Loss of function; GOF, Gain of function; AP1S3,
Adaptor related protein complex 1 subunit sigma 3; CARD14, Caspase recruitment domain family member 14; SERPINA3, Serpin peptidase
inhibitor clade A member 3.

KODALI et al.
8.3 | AP1S3 mutation
AP1S3 loss-­of-­function mutations are also implicated in GPP patho-
genesis. These genetic abnormalities impair the AP-­1 complex subu-
nit 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 build-
­up.60 Large quantities of p62 cause increased NFκB signalling, lead-
ing to the overexpression of IL-­36α and subsequent overactivation
21,46
of the IL-­36 pathway.
Like CARD14 variants, AP1S3 variants were found in fewer GPP
cases than IL36RN. A study examining genetic differences in psori-
asis patients found that 4 out of the 251 GPP patients tested had
AP1S3 mutations. Out of those 4 GPP patients, 2 had both AP1S3
and IL36RN disease alleles.40 AP1S3 mutations across GPP, PPP
and ACH may have different penetrance based on sex-­specific fac-
tors, as almost all patients with AP1S3 disease alleles were female
(p = 0.06).40
8.4 | MPO deficiency
Deficiency in the MPO gene encoding myeloperoxidase has only
recently been associated with GPP.49 Myeloperoxidase is a haem-­
containing peroxidase released by neutrophil granulocytes that ca-
talyses 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
62
component of the innate immune response. MPO deficiency cor-
related with the activity of IL-­36-­activating neutrophil proteases,
stimulating the inflammatory IL-­36 pathway.8 Phagocytosis assays
of human and mouse cells with MPO deficiencies have revealed al-
tered neutrophil function and impaired efferocytosis, leading to a
8,63
prolonged neutrophil presence in inflammatory skin. Further
phenotypic analysis showed that individuals with MPO mutations
more frequently had GPP with palmoplantar pustular psoriasis
(PPPP), tongue involvement, and family history of inflammatory skin
8
or joint diseases. Additionally, a younger age of onset was directly
8
correlated with a higher number of mutant MPO alleles.
8.5 | 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 preva-
lence.64 Normal expression of the SERPINA3 gene produces the
|
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1209
Serpin Peptidase Inhibitor Clade A Member 3 (SERPINA3) protein.
SERPINA3 inhibits the activity of cathepsin G, the primary serine
protease involved in cleaving and activating IL-­36 precursors. It is
postulated that with non-­functional SERPINA3, there is a continu-
ous hyperactivation and build-­up of functional IL-­36, leading to the
unregulated stimulation of the pro-­inflammatory IL-­36 pathway.65
Although implicated in GPP, SERPINA3 genetic deletions seem to be
relatively rare and present in only a few patient reports.66
9 | M A N AG E M E NT
Treatment guidelines for GPP are not well-­established, and only
one FDA-­approved GPP-­specific medication, spesolimab, is cur-
rently approved for use in the United States. Recently, the European
Commission has approved spesolimab for use in adults with GPP
flares in the European Union (EU) countries.67 Apart from the United
States and the EU countries, spesolimab and additional IL-­36 path-
way inhibitors are not currently approved for use globally. Biologic
and non-­biologic treatments not specific to GPP also exist (Figure 2).
It should be noted that each of the treatment options discussed fol-
low conservative measures and could include inpatient admission
and supportive care in necessary circumstances. Due to varying co-
morbidities and levels of disease associated with GPP, treatments
should also be personalized.
9.1 | Anti-­IL-­36 pathway therapy
Antagonistic anti-­IL-­36 receptor antibodies can be used to inhibit
the signalling pathway that causes active GPP flares and can be ef-
fective even in cases with no deleterious IL36RN mutations.63 The
anti-­IL-­36 receptor antibody spesolimab was recently approved to
treat acute GPP in the United States and functions by inhibiting the
IL-­36R, which prevents the IL-­36 inflammatory cascade (Figure 3).
One randomized controlled trial demonstrated that a 900 mg intra-
venous dose of spesolimab increased lesional clearance in a patient
cohort with active GPP flares after 1 week. Progress was measured
via the Generalized Pustular Psoriasis Physician Global Assessment
(GPPGA), which relies on professional evaluation of subjects' skin
condition in three categories: erythema, pustules and scaling/crust-
ing.80 Scores for each category range from 0 to 4, with 0 indicat-
ing no visible symptoms and 4 indicating severe symptoms.81 After
one week, 43% of patients receiving spesolimab compared to 11%
of control patients achieved a GPPGA total score of 0 or 1, respec-
tively. 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.
For rapid treatment of acute severe flares of GPP, a single intra-
venous dose of spesolimab may be effective. Spesolimab is currently
 |

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1210 KODALI et al.

F I G U R E 2 Current GPP treatment therapies. GPP can be managed through a variety of medications that all function differently (rcsb.
org).47,48,68–­73 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, TNF-­α 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.

undergoing a 48-­week safety and efficacy trial for the long-­term
management of GPP.10 Long-­term management options being as-
sessed include a 600 mg subcutaneous spesolimab injection with
a 300 mg maintenance dose administered every 4 weeks, a 600 mg
loading dose with a 300 mg maintenance dose administered every
12 weeks and a 300 mg loading dose with a 150 mg maintenance
dose administered every 12 weeks.10
Many other potential anti-­IL-­36 pathway therapies for GPP
are still in development and testing. Imsidolimab is an IL-­36 inhib-
itor currently undergoing a phase 3 clinical trial to investigate the
safety and efficacy of the drug over a 4-­week and 24-­week pe-
riod. One study examined imsidolimab's performance in 8 individ-
uals with GPP over a 1-­year period; patients received 750 mg of
IV imsidolimab on Day 1 and 100 mg of subcutaneous imsidolimab
 |

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KODALI et al. 1211

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.

every 4 weeks until Day 85. 83 It was found that at Week 4, 75% of
patients demonstrated a positive clinical response on the Clinical
Global Impression (CGI) scale; this percentage held constant at
83
Week 16. 2 of the 8 individuals had infections over the study pe-
riod; one individual acquired COVID-­19, and the other acquired a
nosocomial infection. 83
Small molecules that inhibit IL-­36γ are currently being developed
and could be applicable in the treatment of GPP. The endothelin re-
ceptor A antagonist ambrisentan (A-­552) was identified as a potent
inhibitor of IL-­36γ in humans. A-­552 functions by inducing multiple
inhibitory chemical and conformational changes in IL-­36γ, diminish-
ing IL-­36γ's receptor-­binding capability.84 Phenotyping of individuals
who lack the IL-­36R-­encoding gene revealed that they are not se-
verely immunocompromised, further proving that the IL-­36 pathway
85
is a favourable therapeutic target with minimal side effects.
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
79
such as NF-­κB, AP-­1 and STAT3. Inhibiting IL-­1RAcP's ability to
dimerize with IL-­36R could prevent the IL-­36 pathway overactiva-
tion 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
9.2 | TNF-­α inhibitors
TNF-­α is associated with increased production of IL-­36R agonists,
which stimulate the IL-­36 pathway that induces more TNF-­α produc-
tion in a continuous inflammatory loop. TNF-­α 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 TNF-­α 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 improve-
ment 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 12-­
month period, no relapse of GPP or PA symptoms was noted.89
 |
1212
While effective, TNF-­α inhibitors do display adverse effects. In
a Turkish study examining 156 GPP patients, TNF-­α inhibitors were
90
the only biologic GPP treatment that triggered paradoxical GPP.
An estimated 0.6%–­5.3% of patients treated with TNF-­α inhibitors
develop paradoxical GPP, and the most common drug associated
91,92
with paradoxical GPP was infliximab.
9.3 | IL-­17 inhibitors
IL-­17A and IL-­17RA inhibitors include the medications secukinumab,
ixekizumab and brodalumab. All three of these biologics are ap-
proved for use with GPP patients in Japan, and brodalumab is also
47,93
approved for use in Thailand and Taiwan.
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 broda-
95,96
lumab's use. 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 pro-
94
gram designed to manage the risk of suicidal thoughts and actions.
Brodalumab should not be prescribed to individuals with a history of
suicidal thoughts.94
Secukinumab and ixekizumab have also been established as ef-
fective treatments for GPP. Secukinumab was found to be effective
in a phase 3 trial involving 12 patients with GPP.97 After 3 to 4 weeks,
72.7% of patients achieved a Psoriasis Area and Severity Index (PASI)
score of at least 75 and after 16 weeks, 83.3% of patients achieved a
98
PASI score of at least 75. Out of 5 individuals with GPP who were
assessed in a phase 3 trial for ixekizumab, 2 (40%) had completely
clear skin and 4 (80%) had achieved a PASI score of at least 75 after
97
12 weeks. All patients treated with ixekizumab had an improve-
97
ment in their PASI score. The most commonly reported adverse
47,93,97,98
event across all three IL-­17 inhibitors was nasopharyngitis.
9.4 | IL-­23 inhibitors
IL-­23 regulates the synthesis of IL-­17, which in turn stimulates the syn-
49
thesis of pro-­inflammatory IL-­36R agonists, further over-­activating
the IL-­36 pathway. IL-­23 inhibitors guselkumab and risankizumab are
6,47,99
approved for use in Japan. A Japanese phase 3 study evaluat-
ing the efficacy and safety of guselkumab found that out of 10 GPP
patients treated with 50 mg guselkumab, 77.8% achieved treatment
success after 16 weeks of treatment. However, 28.6% of all patients
treated with guselkumab (n = 21) acquired nasopharyngitis over a
52-­week period of treatment.100 A phase 3 trial for risankizumab
demonstrated that a 150 mg subcutaneous dose resulted in 88% of
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KODALI et al.
225 Japanese subjects achieving a sPGA score of 0 or 1; serious in-
fections were not linked to risankizumab treatment.99
9.5 | Steroids
Other medications that have been used to manage GPP include sys-
temic steroids. Although systemic corticosteroids can quickly alle-
viate 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 fre-
quently brought about increasingly severe GPP flares101 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 beta-
methasone dipropionate is absorbed through compromised skin.102
Symptomatic treatment can also be employed to alleviate symp-
toms 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.
9.6 | Retinoids
Retinoids were found to inhibit the differentiation of Th17 cells
while also inducing T regulatory cell expression, promoting an anti-­
inflammatory response.104 Retinoids may also limit the production
of TNFα, IL-­1 and IL-­6 .47,105 Acitretin can be effective in address-
ing GPP, but when given as a maintenance dosage (10–­3 0 mg/day),
patients reported mild recurrence of symptoms at follow-­up.106
Acitretin is teratogenic, which is also a concern when prescrib-
ing to individuals of child-­b earing 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, reti-
noic 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

KODALI et al.
A notable concern when prescribing isotretinoin is immediate avail-
ability; 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,
47
isotretinoin is faster-­acting than other GPP medications.
9.7 | 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 re-
sponses 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 effec-
tive in addressing acute GPP episodes for some patients. In one ret-
roactive 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 con-
5
trolling an outbreak. The use of cyclosporine in the management of
chronic GPP is less effective, with recurring flares being only par-
tially controlled and the potential for hypertension to develop with
extended use.5
9.8 | 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 dis-
ease or a diabetes mellitus comorbidity; methotrexate should be
used with caution in these patients.115 Furthermore, patients un-
dergoing 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 preg-
nant 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
|
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1213
applicable for patients with GPP who have been treated with acitre-
tin and had minimal improvement or adverse side effects.
9.9 | Apremilast
Apremilast is a phosphodiesterase-­4 (PDE4) inhibitor. PDE4 inhi-
bition has been shown to raise cyclic-­AMP (cAMP) levels and de-
crease 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
9.10 | 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 bet-
ter 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 non-­
specific therapies or supportive care available for use. In many coun-
tries, 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 speso-
limab, 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
 |
1214
are licensed for the treatment of PV and GPP in Japan.124 TNF-­α
inhibitors and IL-­23 inhibitors are also approved for the treat-
ment 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 biolog-
ics are, however, less effective in treating GPP than in PV. Common
non-­biologic systemic agents used for the treatment and manage-
ment of GPP in Europe include acitretin, cyclosporine A and meth-
otrexate. 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 cala-
mine is used to minimize pustules, decrease irritation and maintain
skin hygiene during outbreaks.125 Herbal topical and systemic ther-
apies are often used on their own or in combination with Western
125
treatments.
It is vital that additional medications that work quickly to alle-
viate 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 man-
agement of the condition.
10 | M A J O R O PE N Q U E S TI O N S
Numerous gaps of knowledge exist in the understanding of GPP.
One notable concern when managing patients with GPP is predict-
ing and recognizing acute flares as soon as possible. Rapid recogni-
tion of acute illness can minimize the duration and severity of patient
discomfort and reduce the risk of complications arising from disease
31
pathology. Methods of detecting flares should involve repeated
clinical and patient-­reported assessment and documentation of the
patient's baseline skin condition, allowing for small changes to be
recognized and addressed quickly. Longitudinal studies of individu-
als with GPP could be carried out to monitor lifestyle factors, skin
condition and other symptoms; this will allow for more accurate pre-
diction and identification of flares.
Furthermore, variations in response to spesolimab and non-­
biologic therapies across different ethnic groups should be mea-
31
sured and quantified. Different ethnic groups have different allele
frequencies of mutations across the range of different genes impli-
19,22
cated in the pathogenesis of GPP. 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 ef-
ficacy of a particular medication in order to increase cohort sizes.
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KODALI et al.
The approval of spesolimab in the United States has brought
about a need for updated guidelines for the treatment and manage-
ment of GPP.31,74 Experiments that provide more robust data com-
paring 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 child-­
bearing 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 be-
coming pregnant or discontinue therapy prior to conceiving. Non-­
teratogenic therapies should be investigated and assessed for use
in pregnant individuals. Prompt development and approval of addi-
tional biologic therapies for the treatment and management of GPP
may help to address this issue.
11 | CO N C LU S I O N S A N D PE R S PEC TI V E S
GPP is a severe inflammatory condition that can be life-­threatening.105
During flares, skin is compromised such that patients are at signifi-
cant risk of hypothermia and infection, particularly in a hospital en-
vironment. 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, includ-
ing 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 dis-
tress, and minimize the severity of GPP-­related complications. 31
Maintenance therapies that can be used long-­term (with min-
imal side effects) and are effective in preventing flares are also
needed. 31 Although treatments are limited, the anti-­IL-­36 recep-
tor 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 pe-
riod 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 spe-
solimab, this medication may be a suitable alternative for address-
ing 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

KODALI et al.
United States.31 Updated guidelines for the management of GPP
should be developed with biologic agents in mind.31
AU T H O R C O N T R I B U T I 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.
AC K N OW L E D G M E N T S
None.
F U N D I N G I N FO R M AT I O N
None.
C O N FL I C T O F I N T E R E S T S TAT E M E N T
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 cre-
ated or analyzed in this study.
F I N A N C I A L D I S C LO S U R E S
None.
R E P R I N T R EQ U E S T S
None.
ORCID
Nilesh Kodali https://orcid.org/0000-0003-2092-9469
Isabella Blanchard https://orcid.org/0000-0002-4995-031X
Sruthi Kunamneni https://orcid.org/0000-0002-6443-6079
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How to cite this article: Kodali N, Blanchard I, Kunamneni S,
Lebwohl MG. Current management of generalized pustular
psoriasis. Exp Dermatol. 2023;32:1204-1218. doi:10.1111/
exd.14765