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January 2023 Volume 7 Issue 1

BRIEF ARTICLE

New Onset Generalized Pustular Psoriasis Rapidly Improved
with IL-36 Blockade

Meredith Burns, BS1, Timothy Orlowski, MD2, Hoang Ho-Pham, MD2, Carly Elston, MD2*, Boni
Elewski, MD2*

*Drs. Elston and Elewski contributed equally to this article

1Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL
2Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL

Generalized pustular psoriasis is an
uncommon variant of psoriasis characterized
by diffuse eruption of sterile pustules with
potential for sepsis and organ failure. A
paucity of reliably efficacious therapeutics
has made this condition difficult to treat.
Interleukin-36 (IL-36) receptor antagonists
are emerging as a promising therapy for
pustular psoriasis providing rapid and
efficacious response. We present a case of
generalized pustular psoriasis with complete
response to spesolimab, an IL-36 receptor
antagonist monoclonal antibody that recently
became the first FDA-approved therapy for
this condition. Physicians should be familiar
with this now treatable disorder.

A 60-year-old female with past medical
history of plaque psoriasis and psoriatic
arthritis treated with guselkumab 100mg
every 8 weeks presented to the emergency
department with an acute generalized
pustular dermatosis that developed after she
received intramuscular triamcinolone and
oral methylprednisolone to treat a
presumable morbilliform drug eruption that
developed after she was given oral
clindamycin for paronychia. Both her
cutaneous and articular disease had been
well-controlled on guselkumab since
February 2021 with minimal localized
cutaneous disease after failing therapy with
adalimumab, etanercept, ustekinumab,

ABSTRACT

Generalized pustular psoriasis is a relatively rare variant of psoriasis characterized by diffuse
eruption of sterile pustules on an erythematous background. Untreated flares can result in life-
threatening complications including sepsis and organ failure. Generalized pustular psoriasis
has historically proven challenging to treat with an unpredictable clinical course and paucity of
reliably efficacious treatment options. Until recently, there have been no FDA-approved
therapies for generalized pustular psoriasis in the United States. In September 2022, the IL-
36 receptor antagonist spesolimab became the first FDA-approved treatment for generalized
pustular psoriasis in adults. We present a case of generalized pustular psoriasis with
complete and rapid response to spesolimab.

INTRODUCTION CASE REPORT

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January 2023 Volume 7 Issue 1

secukinumab, and ixekizumab. The patient
had rapid generalization of her skin lesions
with severe skin tenderness, fever of
103.9°F, chills, tachycardia, and
leukocytosis. She was admitted to the
intensive care unit.

Physical examination was notable for diffuse
coalescing and isolated pustules within a
background of erythema involving the face,
neck, trunk, groin, upper extremities, and
lower extremities. There was significant
edema of the face, trunk, and extremities.
Two 4mm punch biopsies were performed
from the left abdomen and left thigh.
Histologic sections demonstrated subcorneal
and intraepidermal spongiform pustules
consistent with pustular psoriasis.

The patient was treated with a single
intravenous infusion of spesolimab 900mg in
addition to triamcinolone 0.1% ointment and
hydrocortisone 1% cream. She had rapid and
remarkable improvement within 18 hours of
receiving spesolimab with almost complete
resolution of superficial pustules and

background erythema on the face, neck,
trunk, and extremities. Physical examination
40 hours following spesolimab treatment
showed continued improvement with
complete resolution of all remaining pustules.
The infusion was well-tolerated, and the
patient reported no adverse effects. She was
discharged home two days post-infusion with
a plan for 1 month follow-up in outpatient
dermatology clinic, continuation of topical
treatment, and continuation of guselkumab.

Generalized pustular psoriasis is a relatively
rare and potentially fatal autoinflammatory
dermatologic condition with marked impacts
on patient quality of life. Acute generalized
pustular psoriasis commonly presents with
accompanying systemic symptoms including
fever, chills, malaise, and severe pain due to
underlying systemic inflammation. Untreated
flares can result in life threatening
complications including sepsis, renal failure,
hepatic failure, and cardiorespiratory failure.1
Corticosteroid use and withdrawal is a known
trigger for generalized pustular psoriasis
flares, and other potential triggers include
smoking, pregnancy, stress, infections,
lithium, TNF-alpha inhibitors, and
nonsteroidal anti-inflammatory drugs.2,3,4

DISCUSSION

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While the immunopathogenesis involved in
the development of generalized pustular
psoriasis is complex, studies have identified
the IL-36 pathway as a key element in the
pathogenesis of this disorder.2
Overexpression of IL-36, or a loss-of-function
mutation in the IL-36 receptor antagonist IL-
36RA, leads to increased levels of
proinflammatory mediators and activation of
IL-36 receptors on skin cells.5,6 IL-36, which
belongs to the IL-1 superfamily of cytokines,
is vital to the homeostasis of the innate
immune system. These family members
include several cytokines, receptors, and
accessory proteins that, when disturbed, can
result in inflammatory dermatoses such as
psoriasis.7 Activation of IL-1 cytokines with
their receptors results in downstream action
of nuclear factor kappa B, mitogen-activated
protein kinases, and ultimately
proinflammatory gene expression.7 In
pustular psoriasis, unbalanced production of
IL-1 and IL-36 contribute to
autoinflammation, innate immune system
activation, and neutrophilic infiltration of the
epidermis, which leads to the clinical
presentation of sterile pustules within a
background of erythema.8

Generalized pustular psoriasis has
historically proven challenging to treat with an
unpredictable clinical course characterized
by persistent disease or intermittent relapsing
flares. With previously available treatment
options, a quarter of patients experience
persistent pustular lesions despite systemic
therapy.1 Because of the severity of this
disease and risk of sepsis and end-organ
dysfunction, flares are generally managed in
the inpatient setting with a 10 day average
length of admission.1,2 Until recently, there
have been no approved therapies for
generalized pustular psoriasis in the United
States with a paucity of evidence-based
treatment options. Medical management of

the disease has included the use of
cyclosporine, systemic retinoids,
methotrexate, and biologic agents.9
However, these treatments are often far less
effective for pustular psoriasis compared to
standard plaque psoriasis and can be
associated with a multitude of adverse effects
including hypertension, renal toxicity, and
teratogenicity.10

In September 2022, the IL-36 receptor
antagonist spesolimab became the first FDA-
approved treatment for generalized pustular
psoriasis in adults. Spesolimab is a
humanized monoclonal antibody that blocks
the IL-36 receptor, thus inhibiting the ability of
IL-36 to bind and initiate proinflammatory
cascades.10 While the exact impact of
reduced IL-36 receptor activity in generalized
pustular psoriasis is undetermined, rapid and
sustained improvement in clinical symptoms
and inflammatory markers including C-
reactive protein was demonstrated in Effisayil
phase 1 and 2 trials examining the efficacy of
spesolimab.11,12 Dosing of spesolimab in the
treatment of generalized pustular psoriasis
for adults is one 900mg intravenous infusion,
then an additional 900mg infusion may be
given one week later if the flare persists.12
Imsidolimab is another IL-36 receptor
antagonist that is currently in phase 3 trials
and has shown promising results for the
treatment of pustular psoriasis.8

Generalized pustular psoriasis should be
considered in the differential diagnosis of any
generalized pustular eruption. Because of
associated fever and systemic symptoms
and the pustular nature of the disease,
generalized pustular psoriasis is often
misdiagnosed as an infectious disorder.
Primary care physicians, hospitalists, and
emergency medicine physicians, who are

CONCLUSION

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often seeing these patients at time of initial
presentation, should be familiar with this now
treatable disorder. This case highlights the
potential of IL-36 inhibitors to improve
morbidity and mortality and shorten the
duration of hospital admissions for patients
with generalized pustular psoriasis. By
targeting proinflammatory cytokines involved
in the development of generalized pustular
psoriasis, this emerging therapeutic provides
rapid and effective response with less toxicity
than existing therapies.

Conflict of Interest Disclosures: BE disclosures
include: Clinical Research Support-research funding
to University: Abbvie, Anaptys-Bio, Boehringer
Ingelheim, Bristol Myers Squibb (BMS), Celgene,
Incyte, Leo, Lilly, Merck, Menlo, Novartis, Pfizer,
Regeneron, UCB, Sun, Valeant (Ortho dermatology),
Vanda; Consultant-received honorarium: Amgen,
Arcutis, Boehringer Ingelheim, BMS, Celgene, Leo,
Lilly, Novartis, UCB, Valeant (Ortho dermatology). All
other authors declare no conflicts of interest.

Funding: None

Corresponding Author:
Boni Elewski, MD
Department of Dermatology
University of Alabama at Birmingham
Email: belewski@uabmc.edu

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