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May 2022 Volume 6 Issue 3

BRIEF ARTICLE

Hydroxychloroquine and Acute Generalized Exanthematous
Pustolosis

Justine Galambus, BS1, Atefah Vafa, MD2

1 Morsani College of Medicine, University of South Florida, Tampa, FL
2 Department of Rheumatology, University of South Florida, Tampa, FL

Acute generalized exanthematous
pustulosis (AGEP) is a rare, potentially
lethal, cutaneous reaction precipitated by
drugs in more than 90% of cases,1 with the
most common triggers being pristinamycin,
aminopenicillins, quinolones,
(hydroxy)chloroquine, sulfonamides,
terbinafine, and diltiazem.1 AGEP typically
presents within one day of treatment after
antibiotic exposure versus eleven days after
other drugs, including hydroxychloroquine
(HCQ, Plaquenil).1 AGEP presents with
innumerable pinhead-sized pustules arising
on a diffuse erythematous background and
are reported to localize in intertriginous
zones, the trunk, and upper extremities.2
Diagnostic criteria outside of a pustular
eruption include a fever, neutrophilia with or
without mild eosinophilia, subcorneal or
intraepidermal pustules on skin biopsy, and
spontaneous resolution in less than 15
days.1 Sidoroff et al developed a validation

scale founded in these criteria to aid
clinicians in the diagnosis of AGEP.
The first step in drug-induced AGEP
treatment is withdrawal of the culprit drug.3
Though spontaneous resolution without
intervention is reported,4 first-line therapy is
steroids, recurrent or refractory cases can
be treated with cyclosporin,5 etretinate,6 or
dapsone7. Though the reaction can be very
disconcerting and uncomfortable for the
patient, the general prognosis is good with
the overall mortality rate of up to 5%;2 those
with the highest risk have comorbidities.8
HCQ is an antimalarial medication that is
frequently used as an immunosuppressive.
HCQ-precipitated AGEP is predominantly
reported in the context of HCQ’s
immunosuppressive action, most commonly
when used to treat Rheumatoid Arthritis,9
Sjogren’s Syndrome,5 and Systemic Lupus
Erythematous.6 However, with the increased
use of HCQ as an antiviral for treatment of
COVID-19, several cases of AGEP have
been reported.10 AGEP tends to affect
women, and HCQ-precipitated AGEP

ABSTRACT

Acute generalized exanthematous pustulosis (AGEP) is a rare, potentially lethal, cutaneous reaction
most commonly precipitated by drugs. Removal of the offending drug or treatment of the underlying
infection usually results in recovery, though corticosteroids are often used to bolster treatment. We
report a case of hydroxychloroquine-induced AGEP in an adult female. Though removal of
hydroxychloroquine (HCQ) did largely resolve her rash, she continued to require corticosteroids over
200 days after she first began taking HCQ.

INTRODUCTION

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May 2022 Volume 6 Issue 3

certainly follows that pattern as evidenced
by this literature review. However, this can,
at least in part, be attributed to the common
indications for HCQ predominantly affecting
women. The overall incidence rate of AGEP
is between 1 to 5 cases per million per year
based on the EuroSCAR study, however,
this is reported with the caveat that reliable
data is missing.1 The prevalence of HCQ-
precipitated AGEP has not been studied.
HCQ-precipitated AGEP is associated with a
delayed onset as well as recalcitrant course,
leading to the proposal of a new
classification, generalized pustular figurate
erythema (GPFE).7 GPFE presents as a
sudden eruption of pruritic, erythematous
papules on the face, with concurrent fever
and neutrophilic leukocytosis. There have
only been two reports of death following
HCQ-precipitated AGEP; however, both
were COVID-19 patients who died following
COVID19-attributed pulmonary emboli.

A 38-year old African America female with a
prior history of eczema presented with a
diffuse desquamating rash with a prior
medical history of recently diagnosed
systemic lupus erythematous (SLE),
arthritis, intermittent parotid swelling and dry
mouth, and previous pustular palmar rashes.
The patient was originally prescribed
hydroxychloroquine 200 mg BID for
treatment of her SLE. An antibody panel
revealed elevated Anti-Nuclear Antibodies,
anti-SSA and anti-SSB antibodies.
Rheumatoid factor, anti-dsDNA antibodies,
anti-Smith antibodies, and anti-SCL-70
antibodies were negative.
Biopsy showed a spongiotic epidermis with
hyperkeratosis, variable loss of the granular
layer, and scattered corneal pustules. The
dermis has a mild inflammatory neutrophilic
infiltrate with scattered eosinophils. Gram

staining, GMS (Gomori methenamine silver,
used to detect fungi) and PAS (Periodic
Acid-Schiff, also can be used to detect fungi)
stains were negative. Immunofluorescence
for IgG, IgA, IgM, C3, fibrin, and albumin
were also negative. The biopsy findings
were consistent with AGEP and ruled out
SJS/TEN.

Approximately two weeks after beginning
HCQ, the patient noted a diffuse rash
covering her body; she did not note where
the rash began. Upon admission, she was
found to be afebrile with a rash on the trunk
and bilaterally on the upper and lower
extremities, sparing mucosal sites. HCQ
was stopped owing to suspected drug
reaction, and after four days, the patient was
discharged with prednisone. Prior to
discharge, the patient developed urticarial
lesions around her eyes that were
determined not to be related to AGEP.
Following discharge and HCQ
discontinuation, she had worsening
periorbital urticaria and swelling, as well as
worsening pruritic, painful desquamating
rash with rash on her upper extremities. She
eventually began experiencing some relief
with continued prednisone. Approximately
six months after initial admission, the patient
rash was noted to have new pustular rashes
over the wrists, abdomen, and face.
Her subsequent disease course and
treatment is summarized in Figure 1.

Hydroxychloroquine is associated with a
distinct form of AGEP, prompting
consideration of a distinct classification.
Typical AGEP diagnostic criteria include of a
pustular eruption, fever, neutrophilia with or
without mild eosinophilia, subcorneal or
intraepidermal pustules on skin biopsy, and
spontaneous resolution in less than 15

CASE REPORT

DISCUSSION

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Figure 1. Timeline showing the disease course of the patient’s hydroxychloroquine-induced AGEP

days.1 The patient here presented with a
pustular eruption with neutrophilia, mild
eosinophilia, and intraepidermal pustules on
biopsy. However, the patient was notably
afebrile, and resolution was not achieved by
day 30. It is unclear when the patient
experienced initial full resolution of her rash.
Hydroxychloroquine is notable for a long
half-life, approximately 40-50 days.11 It takes
approximately 5-6 half-lives to significantly
eliminate a drug, meaning that it could take
upwards of 200 days in order to clear HCQ.
This could explain why AGEP is notably
recalcitrant and can last longer than the
typical 15-day resolution when secondary to
HCQ use. Though HCQ-induced AGEP can
have spontaneous resolution, prednisolone
or prednisone is often used to ease
symptoms as with this patient. Prednisone
was noted to have the dual benefit of aiding
with the patient’s arthritis as well.

While this was not the case for this patient,
of note is the use of HCQ in treatment of
COVID-19. Though no longer
recommended,12 some physicians and
patients may be inclined to pursue HCQ as
treatment for COVID-19. Though the deaths
following HCQ-induced AGEP were
attributed to pulmonary emboli, it is
important for patients to understand AGEP
as a potentially severe side effect. In
particular, the longer course and pain

associated with the rash may significantly
impact patient well-being long after potential
COVID-19 resolution. Therefore, this should
be discussed as part of an informed consent
with patients who desire treatment with
HCQ.

Conflict of Interest Disclosures: None

Funding: None

Corresponding Author:
Justine Galambus, BS
Morsani College of Medicine
University of South Florida
560 Channelside Dr
Tampa, FL 33602, USA
Email: galambus@usf.edu

References:
1. Sidoroff A, Dunant A, Viboud C, et al. Risk

factors for acute generalized exanthematous
pustulosis (AGEP)-results of a multinational
case-control study (EuroSCAR). Case Control
Study. Br J Dermatol. Nov 2007;157(5):989-96.
doi:10.1111/j.1365-2133.2007.08156.x

2. Roujeau JC. Clinical heterogeneity of drug
hypersensitivity. Review. Toxicology. Apr 15
2005;209(2):123-9.
doi:10.1016/j.tox.2004.12.022

3. Hoetzenecker W, Nägeli M, Mehra ET, et al.
Adverse cutaneous drug eruptions: current
understanding. Review. Semin Immunopathol.
Jan 2016;38(1):75-86. doi:10.1007/s00281-015-
0540-2

4. Evans CC, Bergstresser PR. Acute generalized
exanthematous pustulosis precipitated by
hydroxychloroquine. Case Report. J Am Acad
Dermatol. Apr 2004;50(4):650-1.
doi:10.1016/s0190-9622(03)02733-6

CONCLUSION

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5. Castner NB, Harris JC, Motaparthi K.
Cyclosporine for corticosteroid-refractory acute
generalized exanthematous pustulosis due to
hydroxychloroquine. Case Report. Dermatol
Ther. Sep 2018;31(5):e12660.
doi:10.1111/dth.12660

6. Matsuda-Hirose H, Sho Y, Yamate T, et al. Acute
generalized exanthematous pustulosis induced
by hydroxychloroquine successfully treated with
etretinate. Case Report. J Dermatol. Feb
2020;47(2):e53-e54. doi:10.1111/1346-
8138.15185

7. Schwartz RA, Janniger CK. Generalized pustular
figurate erythema: A newly delineated severe
cutaneous drug reaction linked with
hydroxychloroquine. Article. Dermatol Ther. May
2020;33(3):e13380. doi:10.1111/dth.13380

8. Szatkowski J, Schwartz RA. Acute generalized
exanthematous pustulosis (AGEP): A review and
update. Review. J Am Acad Dermatol. Nov
2015;73(5):843-8.
doi:10.1016/j.jaad.2015.07.017

9. Pearson KC, Morrell DS, Runge SR, Jolly P.
Prolonged pustular eruption from
hydroxychloroquine: an unusual case of acute
generalized exanthematous pustulosis. Case
Report. Cutis. Mar 2016;97(3):212-6.

10. Delaleu J, Deniau B, Battistella M, et al. Acute
generalized exanthematous pustulosis induced
by hydroxychloroquine prescribed for COVID-19.
Case Report. J Allergy Clin Immunol Pract. Jun 7
2020;doi:10.1016/j.jaip.2020.05.046

11. Schrezenmeier E, Dörner T. Mechanisms of
action of hydroxychloroquine and chloroquine:
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Rheumatol. Mar 2020;16(3):155-166.
doi:10.1038/s41584-020-0372-x

12. Elavarasi A, Prasad M, Seth T, et al. Chloroquine
and Hydroxychloroquine for the Treatment of
COVID-19: a Systematic Review and Meta-
analysis. J Gen Intern Med. Nov
2020;35(11):3308-3314. doi:10.1007/s11606-
020-06146-w