A preview of this full-text is provided by Wiley.
Content available from British Journal of Clinical Pharmacology
This content is subject to copyright. Terms and conditions apply.
LETTER TO THE EDITOR
Extensive hard palate hyperpigmentation associated with
chloroquine use
A 66-year-old woman diagnosed clinical manifestation of
extensive hard palate hyperpigmentation is presented. Due
to historic of rheumatoid arthritis and use of chloroquine
phosphate for 3 years, exogenous hyperpigmentation asso-
ciated with the drug was included among the possible diag-
noses. Incisional biopsy was performed and the
histopathological exam confirmed exogenous hyper-
pigmentation compatible with chloroquine use. The patient
was referred to the rheumatologist and the ophthalmolo-
gist for evaluation of the continuity of the chloroquine use.
After one year of follow-up, no changes were seen in the
hyperpigmentation nor other clinical changes. Hyper-
pigmentation of the hard palate by the use of chloroquine
is one of the adverse effects of the chronic use of this drug
and does not require specific treatment. The adequate
anamnesis and the knowledge about the adverse effects of
the drug allowed an adequate therapeutic approach in
the case.
1|INTRODUCTION
Pigmentary changes in the oral mucosa may be caused by many
medications, including antimalarial drugs (chloroquine phosphate,
hydroxychloroquine, quinidine and quinacrine), tranquilizers (chlor-
promazine), chemotherapeutic drugs (doxorubicin, busulfan and cyclo-
phosphamide), antiretroviral agents (AZT and ketoconazole),
antibiotics (minocycline) and laxatives (phenolphthalein).
1
The patho-
genesis underlying drug pigmentation can be categorized as arising
from the deposition of metabolites or drugs in the dermis and epider-
mis, melanin deposition with or without melanocyte augmentation
and drug-induced post-inflammatory mucosal changes.
2
Chloroquine phosphate, classified as an antimalarial agent due to
its immunosuppressive potential and anti-inflammatory action, is also
used for the treatment systemic lupus erythematosus and rheumatoid
arthritis, in addition to other dermatological conditions.
1
Recent stud-
ies have brought attention to its possible benefit also in the treatment
of patients infected by the novel emerged Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2),
3–5
a pandemic that first
broke out in China and spread rapidly worldwide.
4–6
In so doing, the
use of chloroquine phosphate is expected to increase considerably,
therefore, it is important to recognize its possible side effects.
In this paper, the case of a 66-year-old woman diagnosed with
rheumatoid arthritis and using chloroquine phosphate for 3 years,
with clinical manifestation of extensive hard palate hyperpigmentation
is presented.
2|CASE REPORT
A 66-year-old female patient attended the Outpatient Clinic of the
Mato Grosso Cancer Hospital presenting as main complaint the pres-
ence of extensive palate stain that initially had a light purple hue that
evolved to bluish-black in about one year. The patient reported rheu-
matoid arthritis, cataract, gastroesophageal reflux, hiatal hernia, thy-
roidectomy and use of levothyroxine sodium, chondroitin,
chloroquine, glucosamine, prednisolone and alendronate.
Clinical examination showed a painless, poorly delimited bluish-
black spot on hard palate with approximately 3 cm in diameter, and
teeth with different restorative materials (Figure 1).
In view of the clinical characteristics, incisional biopsy was sched-
uled, with diagnostic hypotheses for tattooing by amalgam, melanoma
and melanocytic nevus. The report of rheumatoid arthritis under con-
tinuous chloroquine therapy 250 mg (1 tablet, once daily) included
exogenous hyperpigmentation associated with the drug among as the
main possible diagnoses. The patient was unable to associate the
duration of medication use and the appearance of pigmentation.
The intervention was uneventful. The collected material was
sent for histopathological examination along with the patient's clini-
cal history. The diagnosis was exogenous hyperpigmentation com-
patible with chloroquine use. The histological sections revealed a
fragment of oral mucosa covered by parakeratinized stratified
paved epithelium. On the lamina propria, in the subepithelial region
and arranged in bands, exogenous black-colored pigments were
noted, which sometimes were phagocytosed by macrophages
(Figure 2).
The patient was referred to her rheumatologist, informing about
the diagnosis. He maintained the medication. She was also referred to
the ophthalmologist for evaluation due to the chloroquine
retinotoxicity potential.
Received: 25 September 2019 Revised: 23 March 2020 Accepted: 27 March 2020
DOI: 10.1111/bcp.14313
Br J Clin Pharmacol. 2020;86:2325–2327. wileyonlinelibrary.com/journal/bcp © 2020 The British Pharmacological Society 2325
The patient has been under follow-up for one year, with no other
clinical changes suggestive of chloroquine adverse effect, and the blu-
ish black palate shows no change in presentation.
3|DISCUSSION
This paper presents the clinical case of a 66-year-old female patient
with extensive 1-year hard palate pigmentation and 1-year follow-up.
Pigmentations of the oral mucosa can be classified as exogenous
when they result from traumatic implantation of materials such as sil-
ver amalgam and graphite and endogenous as a result of red blood cell
destruction or increased melanin production. Oral pigment changes of
endogenous origin are mainly related to the use of tetracycline, min-
ocycline, antimalarial agents, oral contraceptives, chemotherapeutic
agents and some drugs used in AIDS therapy.
7
Chloroquine and other quinine derivatives are drugs used to treat
malaria, cardiac arrhythmia, lupus erythematosus, rheumatoid arthri-
tis
7,8
and possibly in the treatment of patients infected by the novel
emerged coronavirus (SARS-CoV-2).
3,4,9
Oral pigmentations associ-
ated with chronic use of chloroquine are characteristically bluish in
color. Most of the time, only the hard palate is involved, with a
remarkable demarcation between it and the soft palate.
7,8
Chronic
use of such medication may also develop pathological pigmentation of
the face, upper and lower limbs, as well as irreversible retinal dam-
age.
10
Adverse effects of chronic chloroquine use include xerostomia,
skin hyperpigmentation and pruritus. Less commonly, there is mucosal
hyperpigmentation, nail dystrophy, and hair hypopigmentation. At the
stomatological level, areas of bluish-black-blue pigmentation of vary-
ing size and well-circumscribed may appear, usually in the oral mucosa
and hard palate, not affecting the soft palate.
11
In the present case,
the patient was on therapy for rheumatoid arthritis, using chloroquine
for 3 years and presented the oral manifestation an extensive bluish-
black hyperpigmentation limited to the hard palate as the only adverse
effect of the chronic use of the medication.
The diagnosis of chloroquine pigmentation is basically guided by
the history of drug use and the clinical manifestations of the patient.
In typical cases or with incomplete history, a biopsy is performed to
aid the diagnosis. In atypical cases, biopsy is crucial to rule out
melanoma.
12
Given the long-term history of chloroquine, the main
diagnostic hypothesis was drug-induced endogenous oral hyper-
pigmentation. Differential diagnoses are cited as melanocytic nevus,
amalgam tattooing, Addison's disease, vitamin B12 deficiency and
melanoma.
8
Microscopically, hyperpigmentation of the oral mucosa of medici-
nal origin is characterized by an abnormal number of melanocytes in
the epithelium and the presence of pigment granules within the lam-
ina propria, between collagen fibers and within macrophages. When
there are granules in the reticular lamina propria and lack of melanin
deposition in the basal cell layer, it is pointed to the hyper-
pigmentation due to the use of hydroxychloroquine.
13
An incisional biopsy was performed and submitted to histopatho-
logical examination, whose report described the presence of black-
ened exogenous pigments in the lamina propria and subepithelial
region, sometimes phagocytized by macrophages, as well as overlying
epithelium with normal appearance. These characteristics are found in
other cases described previously, confirm the diagnosis of drug-
induced oral pigmentation and rule out the hypothesis of neoplastic
development.
1,14
There is no need for treatment in these cases, and the possibility
of reducing or stopping medication can be evaluated by the rheuma-
tologist. It is also important to refer the patient for ophthalmologist
FIGURE 1 Clinical aspect of the color alteration present in the
hard palate with a diameter of approximately 3 cm and evolution of
1 year
FIGURE 2 A, Histological
sections showing fragment of oral
mucosa coated with
parakeratinized stratified paved
epithelium. B, Exogenous
pigmentation of blackish color
arranged in bands
2326 LETTER TO THE EDITOR
evaluation due to the potential for chloroquine retinotoxicity.
15
The
therapeutic approach adopted in this case report was to refer the
patient to the ophthalmologist, as well as to keep her in periodic den-
tal and rheumatological clinical follow-up.
Professionals shall jointly assess the risks and benefits of
maintaining or stopping medication. As the use of chloroquine phos-
phate is probable to increase, it is important that clinicians know this
uncommon side effect.
4|CONCLUSION
Hyperpigmentation of the hard palate by the use of chloroquine is
one of the adverse effects of the chronic use of this drug and does
not require specific treatment. The adequate anamnesis, the dentist's
knowledge about the adverse effects of the drug and the establish-
ment of differential diagnoses allowed an adequate therapeutic
approach in the case presented and the referral to other medical areas
for multidisciplinary approach.
COMPETING INTERESTS
There are no competing interests to declare.
CONTRIBUTORS
Géssica Vasconcelos Godinho and Ana Luiza Lima Medeiros Paz have
made substantial contributions to the conduction of the clinical case,
acquisition, analysis and interpretation of data;
Elâine Patrícia Alves de Araújo Gomes and Cristiane Loreda Gar-
cia were involved in drafting the manuscript and revising it critically
for important intellectual content;
Luiz Evaristo Ricci Volpato have made substantial contributions
to conception and design of the manuscript; analysis and interpreta-
tion of data; drafting the manuscript and revising it critically for impor-
tant intellectual content.
All authors gave final approval of the version to be published.
Each author participated sufficiently in the work to take public
responsibility for appropriate portions of the content; and agreed to
be accountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work are appro-
priately investigated and resolved.
Géssica Vasconcelos Godinho
1
Ana Luiza Lima Medeiros Paz
1
Elâine Patrícia Alves de Araújo Gomes
2
Cristiane Loreda Garcia
2
Luiz Evaristo Ricci Volpato
2
1
Mato Grosso Cancer Hospital, Brazil
2
University of Cuiabá, Brazil
Correspondence
Luiz Evaristo Ricci Volpato, R. Estev~
ao de Mendonça, 371 apto
501, Goiabeiras, Cuiabá –MT, Brazil CEP 78.032-085.
Email: odontologiavolpato@uol.com.br
ORCID
Luiz Evaristo Ricci Volpato https://orcid.org/0000-0002-2969-1963
REFERENCES
1. Melo-Filho MR, Silva CA, Dourado MR, Pires MB, Pêgo SP,
Freitas EM. Palate hyperpigmentation caused by prolonged use of the
anti-malarial chloroquine. Head Neck Pathol. 2012;6:48-50.
2. Sreeja C, Ramakrishnan K, Vijayalakshmi D, Devi M, Aesha I,
Vijayabanu B. Oral pigmentation: a review. J Pharm Bioallied Sci. 2015;
7(Suppl 2):S403-S408.
3. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral
Res. 2020;177:104762.
4. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease
2019 (COVID-19). Drug Discov Ther. 2020;14(1):58-60.
5. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has
shown apparent efficacy in treatment of COVID-19 associated pneu-
monia in clinical studies. Biosci Trends. 2020;14(1):72-73.
6. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of
optimized dosing Design of Hydroxychloroquine for the treatment of
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin
Infect Dis. 2020. pii: ciaa237
7. Kauzman A, Pavone M, Blanas N, Bradley G. Pigmented lesions of the
oral cavity: review, differential diagnosis, and case presentations.
J Can Dent Assoc. 2004;70(10):682-683.
8. Andrade BA, Padron-Alvarado NA, Muñoz-Campos EM, Morais TL,
Martinez-Pedraza R. Hyperpigmentation of hard palate induced by
chloroquine therapy. J Clin Exp Dent. 2017;9(12):e1487-e1491.
9. Colson P, Rolain JM, Raoult D. Chloroquine for the 2019 novel
coronavirus SARS-CoV-2. Int J Antimicrob Agents. 2020;55(3):105923.
10. Ferrazzo KL, Payeras MR, Surkamp P, Danesi CC. Pathological pig-
mentation of the skin and palate caused by continuous use of chloro-
quine: case report. J Oral Diag. 2017;2(1):1-5.
11. Horta-Bass G. Hiperpigmentación de la mucosa oral y discromia
ungueal inducida por cloroquina. Reumatol Clin. 2017;14(3):177-178.
12. Klenegger CL, Hammond HL, Finkelstein MW. Oral mucosal hyper-
pigmentation secondary to antimalarial drug therapy. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod. 2000;90(2):189-194.
13. Tosios KI, Kalogirou EM, Sklavounou A. Drug-associated hyper-
pigmentation of the oral mucosa: report of four cases. Oral Surgery,
Oral Medicine, Oral Pathology and Oral Radiology. 2018;125(3):
e54-e66.
14. Andrade BA, Fonseca FP, Pires FR, et al. Hard palate hyper-
pigmentation secondary to chronic chloroquine therapy: report of
five cases. J Cutan Pathol. 2013;40(9):833-838.
15. Lerman MA, Nadeem K, Guze KA, Woo SB. Pigmentation of the hard
palate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107:
8-12.
LETTER TO THE EDITOR 2327
Content uploaded by Luiz Evaristo Ricci Volpato
Author content
All content in this area was uploaded by Luiz Evaristo Ricci Volpato on Apr 23, 2020
Content may be subject to copyright.