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Adverse Cutaneous Reactions to Hydroxychloroquine Are More Common in Patients With Dermatomyositis Than in Patients With Cutaneous Lupus Erythematosus
Michelle T. Pelle, MD;
Jeffrey P. Callen, MD
Arch Dermatol. 2002;138:1231-1233.
ABSTRACT
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Background Hydroxychloroquine sulfate and other antimalarial drugs have been used
successfully as adjunctive therapy for patients with cutaneous lesions of
dermatomyositis over the past 20 years. An increased incidence of cutaneous
reactions to hydroxychloroquine has been postulated to occur in patients with
dermatomyositis.
Objective To determine if adverse cutaneous eruptions due to hydroxychloroquine
are more common in patients with dermatomyositis than in those with cutaneous
lupus erythematosus.
Design Retrospective, age-, sex-, and race-matched case-control study.
Setting University-affiliated practice.
Patients The study comprised 42 patients with dermatomyositis (39 adults) and
39 age-, sex-, and race-matched adult patients with lupus erythematosus.
Main Outcome Measures Presence or absence of documented drug eruption due to hydroxychloroquine
exposure.
Results Of 39 patients, 12 (31%) with dermatomyositis developed a cutaneous
reaction to hydroxychloroquine. Among age-, sex-, and race-matched patients
with cutaneous lupus erythematosus, only 1 developed a cutaneous reaction
to hydroxychloroquine. None of the reactions observed in our patients resulted
in serious morbidity or mortality. Additionally, 4 patients with dermatomyositis
who reacted to hydroxychloroquine were treated with oral chloroquine phosphate,
2 of whom also reacted to chloroquine phosphate.
Conclusions When contemplating antimalarial therapy for dermatomyositis, both the
physician and the patient should recognize that non–life-threatening
cutaneous reactions may occur in approximately one third of patients and that
perhaps one half of those who react to hydroxychloroquine will also react
to chloroquine.
INTRODUCTION
DERMATOMYOSITIS (DM) is an idiopathic inflammatory myopathy that has
characteristic cutaneous manifestations including the heliotrope rash, Gottron
papules, photodistributed erythema or poikiloderma, alteration of the cuticles,
and a pruritic scalp dermatitis.1 Treatment
with systemic corticosteroids and immunosuppressive medications usually controls
the inflammation of the muscles, but often the skin disease is not fully controlled.
Hydroxychloroquine sulfate has been reported to improve the cutaneous manifestations
associated with DM.2-5
Cutaneous reactions to antimalarial agents were commonly observed in
the treatment of psoriasis and psoriatic arthritis.6
Similar reactions are unusual in patients with lupus erythematosus (LE). We
have observed disease-specific cutaneous reactions to hydroxychloroquine in
the treatment of DM. To determine whether an increased frequency of cutaneous
reactions to hydroxychloroquine occurs in patients with DM, we reviewed the
records of 68 patients with DM and compared them with a group of age-, sex-,
and race-matched patients with cutaneous LE.
PATIENTS AND METHODS
Approval for research using existing data was received from the Human
Studies Committee of the University of Louisville School of Medicine. A list
of patients with a diagnosis of DM was computer generated from billing records
of the university-affiliated practice. Criteria for the diagnosis of DM were
as follows: characteristic skin manifestations as diagnosed by a dermatologist
and skin biopsy result consistent with DM, with or without positive serologic
findings. Physical examination findings of muscle weakness and/or muscle enzyme
analysis, electromyogram and/or muscle biopsy results consistent with myositis
supported the diagnosis, but we did not require the demonstration of myositis
as a diagnostic criterion. Only patients who had been treated with hydroxychloroquine
at some time during the course of their disease were eligible. Patients may
have been treated by a referring physician or the therapy may have been initiated
upon referral or after other therapies had failed or been demonstrated to
be toxic. A follow-up period of at least 2 months was also required for eligibility.
Similarly, a list of patients with a diagnosis of cutaneous LE was generated
from billing records for use as controls. Criteria for the diagnosis of cutaneous
LE were as follows: characteristic lesions of LE on physical examination by
a dermatologist and characteristic findings on skin biopsy. Patient records
were selected for further review if the patient had been treated with hydroxychloroquine.
Charts of patients with LE were requested from our files and were reviewed
to verify diagnosis, ascertain exposure to hydroxychloroquine, and obtain
the age, race, and sex of the hydroxychloroquine-treated patients. We then
selected 1 such patient to serve as a control for each patient treated for
DM. The control patient was matched by age (±5 years), sex, and race.
Our protocol called for only 1 matched patient, and although there may have
been many other possible matches, these charts were not further reviewed.
Documented cutaneous eruptions to hydroxychloroquine and/or chloroquine
phosphate in both groups within 1 month of initiation of therapy were considered
positive reactors. We also reviewed the medical records for information about
other drug allergies as reported by the patient or observed by a physician
and concomitant drug use at the time of the hydroxychloroquine eruption. All
patients seen were asked, often repeatedly, about drug allergies. Statistical
analysis was performed using the McNemar test on StatXact software (Cytel
Software Corp, Cambridge, Mass). A 2-sided P value
is reported; P<.05 was considered significant.
RESULTS
Eight of the 68 patients qualified as having possible amyopathic DM
based on skin findings, biopsy results, and absence of muscle weakness and
normal test findings of muscle-derived enzymes. The other 60 patients had
evidence of both skin and muscle disease consistent with DM. Of the 68 patients,
42 had been treated with hydroxychloroquine at some time following diagnosis
and were therefore eligible for the study. We were unable to match 3 juvenile
patients with DM with controls, and thus 39 patients were included in our
statistical analysis. Eligible adults with DM ranged in age from 17 to 81
years (mean, 48.8 years). Of the 39 patients, 36 (92%) were women and 37 (95%)
were white. The patients with LE were matched for sex and race, and their
ages ranged from 20 to 76 years (mean, 47.5 years).
Twelve (31%) of the 39 adult patients with DM developed a cutaneous
reaction to hydroxychloroquine (Figure 1).
In comparison, only 1 patient with LE (3%) developed a reaction (P = .006). Combined with the 3 juvenile patients with DM, 14 (33%)
of the 42 patients overall developed an allergic reaction to hydroxychloroquine.
The morphologic features of the cutaneous eruptions were variable. Eleven
reactions (79%) were generalized morbilliform eruptions, often intensely pruritic,
and all began within 3 weeks of the initiation of therapy. Each resolved on
discontinuation of the drug regimen, and many of the patients were treated
with tapering courses of oral prednisone. Three of these patients were subsequently
started on chloroquine therapy. Two tolerated the drug (although 1 later developed
intolerable keratopathy), and 1 developed a morbilliform eruption to chloroquine.
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A, Before the use of hydroxychloroquine sulfate, this patient had
a photodistributed poikiloderma; B, 7 days following the first dose of hydroxychloroquine,
a morbilliform eruption developed. Note the presence of a confluent, erythematous
eruption that is not only in a photodistribution but is now on the breasts
and upper abdomen.
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Of the remaining 3 nonmorbilliform eruptions, 1 patient developed an
erythroderma within 2 weeks of commencing hydroxychloroquine therapy. She
was later given a trial of chloroquine and developed truncal erythema and
pruritus. Another patient developed a widespread blistering eruption that
was diagnosed as Stevens-Johnson syndrome. She was treated successfully with
drug withdrawal and oral prednisone. The final patient developed erythema
and edema in an unspecified distribution. None of the cutaneous eruptions
were associated with serious morbidity or mortality. The 1 cutaneous reaction
in the control patient with LE was morbilliform and resolved on discontinuation
of the drug regimen and a short course of oral prednisone.
Dosages of hydroxychloroquine sulfate were either 200 mg daily or 200
mg twice daily in both the patients with DM and LE. At the time of the eruption,
7 patients were receiving no other therapy (6 patients with DM and 1 with
LE), 5 were also receiving methotrexate and prednisone therapy, 1 was receiving
an antidepressant, and 1 patient's concomitant drug use was not recorded.
Among our 39 adult patients with DM, 8 reported drug allergy to sulfonamides
(3 among the 12 patients who had a reaction to hydroxychloroquine and 5 among
the group that did not). Among the LE patients, 12 reported sulfonamide allergy,
but the patient with the hydroxychloroquine reaction was not allergic to sulfonamides.
COMMENT
Antimalarial agents were first used for lupus in 1894 when Payne7 treated a case of discoid lupus with quinine. It was
not until 1951 that Page8 reported the benefits
of quinacrine for lupus. The use of hydroxychloroquine for the cutaneous manifestations
of DM were first described by Woo et al in 1984.2
They described 7 patients in whom hydroxychloroquine therapy achieved partial
or complete clearance of their skin disease and enabled some patients to reduce
their dosage of corticosteroids. No adverse events related to hydroxychloroquine
were reported in this study. Subsequent case reports and small case series
followed, supporting the use of oral hydroxychloroquine for cutaneous lesions
of DM.3-5
Bloom et al9 provided the first report
of adverse cutaneous reactions to hydroxychloroquine in patients with DM.
They described 2 children in whom the addition of hydroxychloroquine caused
exacerbation of existing skin disease and new eruptions. In 1 patient, worsening
of Gottron papules and a diffuse erythematous, scaly eruption developed over
the posterior neck, thighs, and pretibial skin. The other patient experienced
exacerbation of purple-red plaques on the face, neck, and arms and a new erythematous,
pruritic rash in the axillae. Both patients were using oral corticosteroids
concomitantly. Another series of 9 patients with juvenile DM reported good
effects with hydroxychloroquine and no adverse reactions when it was used
as an adjunct to corticosteroids.4
Over the past 20 years of antimalarial therapy for DM at the University
of Louisville, it was noted that drug reactions to hydroxychloroquine might
occur with an increased frequency. This was in contrast to patients treated
for all types of LE, among whom cutaneous reactions were rare. Our retrospective
analysis confirmed that roughly one third of patients with DM developed a
reaction and that this is notably different from our experience with its use
in patients with cutaneous lesions of LE. We are not able to explain the eruptions
on the basis of the patient having an allergy to sulfonamides or receiving
concomitant drugs; therefore, it may represent a disease-specific idiosyncratic
reaction. There are reports of the successful use of hydroxychloroquine as
a corticosteroid-sparing agent; however, the number of patients reported in
any one series is small, which might account for the previously small numbers
of reactions that have been reported. Fortunately, in none of these cases
were the drug eruptions life threatening, most (79%) were generalized morbilliform
eruptions. In addition, 2 of 4 patients given a trial of chloroquine following
an adverse reaction to hydroxychloroquine developed a cutaneous reaction.
Our results indicate that treatment of adult DM with hydroxychloroquine
is associated with adverse cutaneous events in approximately one third of
cases. Regarding juvenile patients with DM, our series and other series indicate
that their risk of cutaneous reactions is also elevated.9
Patients with cutaneous LE do not experience an increased frequency of such
reactions. In our experience, such information should be discussed with patients
with DM prior to commencing therapy. Alternative therapies do exist; therefore,
the decision to use hydroxychloroquine must be made on a case-by-case basis.
Alternative therapies, such as methotrexate, chlorambucil, mycophenolate mofetil,
and thalidomide, may have inherent risks and adverse effects that justify
the increased risk of cutaneous reactions to antimalarial agents in selected
patients. Although we did not assess the clinical response to hydroxychloroquine
in patients who tolerated the drug, our experience continues to support the
beneficial effects in many patients with DM with refractory cutaneous disease.
AUTHOR INFORMATION
Accepted for publication May 9, 2002.
This work was supported by a grant from the Women's Dermatology Society,
Schaumburg, Ill. Dr Pelle is a Clinical Educator Fellow, and this fellowship
is supported from an unrestricted grant from Paul R. Gross, MD.
Data from this article were presented at the annual meeting of the Medical
Dermatology Society, New Orleans, La, February 21, 2002.
Martin Weinrich, PhD, from the University of Louisville Center for Health
Services and Policy Research, performed the statistical analysis of this article.
A cooperative effort of the Clinical Epidemiology Unit of the Istituto
Dermopatico dell'Immacolata–Istituto di Ricovero e Cura a Carattere
Scientifico (IDI-IRCCS) and the Archives of Dermatology
Corresponding author and reprints: Jeffrey P. Callen, MD, 310 E Broadway,
Louisville, KY 40292, (e-mail: Jefca{at}aol.com).
From the Department of Dermatology, University of Pennsylvania School
of Medicine, Philadelphia (Dr Pelle); and the Department of Medicine, Division
of Dermatology, University of Louisville School of Medicine, Louisville, Ky
(Dr Callen).
REFERENCES
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1. Callen JP. Dermatomyositis. Lancet. 2000;355:53-57.
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9. Bloom BJ, Tucker LB, Klein-Gitelman M, Miller LC, Schaller JG. Worsening of the rash of juvenile dermatomyositis with hydroxychloroquine
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PUBMED
Section Editors:
Michael Bigby, MD,
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass
Rosamaria Corona, DSc, MD, Istituto Dermopatico dell'Immacolata,
Rome, Italy
Damiano Abeni, MD, MPH,
Paolo Pasquini, MD, MPH, Istituto Dermopatico dell'Immacolata
Moyses Szklo, MD, MPH, DrPH, The Johns Hopkins University,
Baltimore, Md
Hywel Williams, MD, Queens Medical
Centre, Nottingham, England
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ABSTRACT
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