1046 Research Letters
OCTOBER 2021
IRB approval status: Reviewed and approved by
Johns Hopkins University IRB (IRB00074049).
Correspondence to: Luis A. Garza, MD, PhD,
Department of Dermatology, Johns Hopkins
School of Medicine, Cancer Research Bldg II, Rm
204, 1550 Orleans St, Baltimore, MD 21287
E-mail: LAG@jhmi.edu
Conflicts of interest
None disclosed.
REFERENCES
1. Fowler J, Jarratt M, Moore A, et al. Once-daily topical
brimonidine tartrate gel 0.5% is a novel treatment for
moderate to severe facial erythema of rosacea: results of
two multicentre, randomized and vehicle-controlled studies.
Br J Dermatol. 2012;166:633-641.
2. Boger WP 3rd. Shortterm ‘‘escape’’ and longterm ‘‘drift.’’ The
dissipation effects of the beta adrenergic blocking agents.
Surv Ophthalmol. 1983;28(suppl):235-242.
3. Gandolfi SA. Restoring sensitivity to timolol after long-term
drift in primary open-angle glaucoma. Investig Ophthalmol Vis
Sci. 1990;31:354-358.
4. Ilkovitch D, Pomerantz RG. Brimonidine effective but may lead
to significant rebound erythema. J Am Acad Dermatol. 2014;
70:e109-e110.
5. Okwundu N, Cline A, Feldman SR. Difference in vasoconstric-
tors: oxymetazoline vs. brimonidine. J Dermatolog Treat. 2021;
32:137-143.
https://doi.org/10.1016/j.jaad.2021.01.098
Adverse cutaneous reactions
secondary to hydroxychloroquine
in patients with dermatomyositis,
lupus erythematosus, and lichen
planopilaris
To the Editor: Studies comparing the frequency of
adverse cutaneous reactions (ACRs) secondary to
hydroxychloroquine (HCQ) therapy in patients with
dermatomyositis (DM) and cutaneous lupus erythe-
matosus (CLE) have shown mixed results. Pelle et al
and Wolstencroft et al both found increased ACRs in
patients with DM.1,2 In contrast, no differences were
found by Gonzalez et al.3 This study had 2 objectives:
first, to evaluate if increased ACRs exist in patients
with DM and, second, to identify specific factors (eg,
history of atopy, other drug allergies, baseline eosin-
ophilia) in patients who developed ACRs secondary
to HCQ therapy that might enable us to predict the
reaction, and thereby avoid it. For this latter purpose,
we sought to increase our dataset by including
patients with lichen planopilaris (LPP), as dermato-
logists frequently prescribe HCQ to these patients.
Based on ICD-10 codes, 1163 patients with DM
seen at Mass General Brigham outpatient
J AM ACAD DERMATOL
dermatology clinics between January 2000 and
December 2019 were identified. Patients for
inclusion had to have an M-33 code that was
recorded at least twice. Individual medical chart
reviews were performed to confirm diagnoses and
to ascertain the use of HCQ. These inclusion criteria
produced a dataset of patients with DM who were
prescribed 200-800 mg HCQ daily. Age and
gender-matched CLE (n ¼ 271) and LPP (n ¼ 74)
controls were then extracted in an identical manner
for comparison in our dataset. After reviewing the
dataset, these criteria yielded 150 patients with CLE
and 36 patients with LPP. Only cases of ACRs
diagnosed by a dermatologist and supported either
clinically or histopathologically were included.
The overall incidence of ACRs due to HCQ
therapy was 4.2% (13/306) and the incidence was
elevated in patients with DM (P \.001, Table I). This
finding of increased incidence of ACRs in patients
with DM is consistent with the findings of Pelle et al
and Wolstencroft et al. However, only 9.2% of
patients with DM who developed ACRs underwent
HCQ therapy, which was lower than that reported by
Pelle et al (31%) and Wolstencroft et al (20.7%).1,2
There were no statistically significant differences in
terms of daily HCQ dose based on actual or ideal
body weight between patients with DM with
HCQ-induced ACRs and those of controls (P ¼ .58).
In contrast to our hypothesis that patients with
DM may also develop more non-HCQ drug allergies,
non-HCQ drug allergies were more common in
patients with CLE (P ¼ .009). Specifically,
hypersensitivity to sulfa was more common in
patients with CLE (P ¼ .004). Baseline eosinophilia
was most frequently found in patients with LPP
(P ¼ .002). Of those who presented with ACRs in
response to HCQ therapy (Table II), those with a
higher mean age were more likely to develop
HCQ-associated ACRs (56.1 versus 46.6, P ¼ .048),
but this significance was lost when multiple
comparison adjustments were performed.
In patients with DM, those on immunosuppres-
sive therapy were less likely to develop ACRs in
response to HCQ therapy than those who were not
(odds ratio, 0.18; P ¼ .02). This is potentially
clinically useful information because if immunosup-
pressant use is a protective factor, the addition of
HCQ only after immunosuppression may help
reduce the risk of HCQ allergy. In conclusion, we
did not identify statistically significant risk factors in
patients with DM that would allow prediction about
which patients develop HCQ-induced ACRs. While
larger than previous studies, this study is limited by
the fact that it is a retrospective study and represents
only a limited sample from a single institution.
J AM ACAD DERMATOL Research Letters 1047
VOLUME 85, NUMBER 4

Table I. Patient characteristics by disease type

Variable DM (N = 120) CLE (N = 150) LPP (N = 36) P value
HCQ-ACR, No. (%) 11 (9.2) 0 2 (5) \.001*
Additional drug allergy, No. (%) 60 (50) 100 (66.7) 17 (47) .009y
Concomitant immunosuppressionz, No. (%) 74 (62) 55 (37) 3 (8) \.001*
Drug class, No. (%)
Sulfa 12 (10) 37 (24.7) 4 (11) .004*
Penicillin 20 (16.7) 33 (22) 8 (22) .22*
Opioid 3 (2.5) 10 (6.7) 3 (8) .14*
Iodinated contrast 1 (0.8) 7 (4.7) 0 .12*
Other, No. (%)
Atopic diseases 14 (11.7) 27 (18.1) 5 (13) .35*
Eosinophiliax 1 (1.6) 1 (2.4) 4 (19) .002*

ACR, Adverse cutaneous reaction; CLE, cutaneous lupus erythematosus; DM, dermatomyositis; HCQ, hydroxychloroquine; LPP, lichen
planopilaris.
*Fisher’s exact test.
y
Pearson chi-square test.
z
Use of at least one immunosuppressant drug.
x
Reported before HCQ exposure.

Table II. Patient characteristics by adverse cutaneous reaction secondary to hydroxychloroquine

Variable No HCQ-ACR (N = 293) HCQ-ACR (N = 13) P value Adjusted P valuex
Age, mean (SD), y 46.6 (17) 56.1 (14) .048* .12
Male gender, No. (%) 32 (10.9) 2 (13) .67y .76
HCQ dose, No. (%)
$400 mg/day 226 (79.9) 6 (66) .02z .1
Number of immunosuppressants, No. (%)
0 160 (54.6) 9 (69)
1 84 (28.7) 1 (7)
2 43 (14.7) 3 (23) .31y .51
3 6 (2) 0
Other
Smoking 82 (29.1) 4 (33) .76y .76

ACR, Adverse cutaneous reaction; HCQ, hydroxychloroquine; SD, standard deviation.

*Two-sample t test.
y
Fisher’s exact test.
z
Pearson chi-square test.
x
False Discovered Rate adjusted for multiple comparisons.

Andressa L. Akabane, MD, and Gideon P. Smith, Conflicts of interest

MD, PhD, MPH None disclosed.

From the Harvard Medical School, Boston, Mas-

sachusetts, and Department of Dermatology,
Massachusetts General Hospital, Boston,
Massachusetts.
Funding sources: None.
IRB approval status: Reviewed and approved by
Partners Human Research Committee (approval
#2014P002301/MGH).
Correspondence and reprint requests to: Andressa L.
Akabane, MD, Harvard Medical School, 25
Shattuck Street, Boston, MA 02115
REFERENCES
1. Pelle MT, Callen JP. Adverse cutaneous reactions to
hydroxychloroquine are more common in patients with der-
matomyositis than in patients with cutaneous lupus erythema-
tosus. Arch Dermatol. 2002;138(9):1231-1233. [discussion: 1233].
2. Wolstencroft PW, Casciola-Rosen L, Fiorentino DF. Association
between autoantibody phenotype and cutaneous adverse
reactions to hydroxychloroquine in dermatomyositis. JAMA
Dermatol. 2018;154(10):1199-1203.
3. Gonzalez CD, Hansen C, Clarke JT. Adverse cutaneous
drug reactions with antimalarials in cutaneous lupus and
dermatomyositis: a retrospective cohort study. J Am Acad
Dermatol. 2019;81(3):859-860.

E-mail: andressa.akabane@gmail.com https://doi.org/10.1016/j.jaad.2021.02.034