Research

Brief Report

Cyclosporine Treatment of Drug-Induced

Hypersensitivity Syndrome
Mark G. Kirchhof, MD, PhD; Aaron Wong, MD; Jan P. Dutz, MD

Supplemental content at
IMPORTANCE Drug-induced hypersensitivity syndrome (DIHS), also known as drug reaction jamadermatology.com
with eosinophilia and systemic symptoms (DRESS) syndrome, is a potentially life-threatening
reaction to medications with a mortality rate up to 10%. Standard therapy involves the use of
systemic corticosteroids with tapering doses extending up to 9 months after the initial
reaction. Alternative treatments for DIHS are needed, especially for patients for whom
systemic corticosteroids are contraindicated.

OBJECTIVE To assess a short course of cyclosporine as first-line therapy for DIHS.

DESIGN, SETTING, AND PARTICIPANTS In this case series, 2 patients referred to the
dermatology service of an academic tertiary care hospital and subsequently diagnosed as
having DIHS were studied from December 1, 2013, through July 31, 2014.

INTERVENTIONS Short course (3-7 days) of cyclosporine.

MAIN OUTCOMES AND MEASURES Clinical and laboratory indicators were examined to
determine the timing and efficacy of cyclosporine treatment.
Author Affiliations: Department of
RESULTS Two cases are reported of drug hypersensitivity reaction that were treated with Dermatology and Skin Science,
cyclosporine, resulting in rapid and significant clinical improvement. The first case involved a University of British Columbia,
Vancouver, British Columbia, Canada
woman in her 40s who developed DIHS after treatment with carbamazepine. A 7-day course (Kirchhof, Wong, Dutz); Division of
of cyclosporine resulted in clinical resolution of the DIHS. The second case was that of a man Dermatology, Department of
in his 30s with minocycline-induced DIHS. A 3-day course of cyclosporine resulted in rapid Medicine, Queen’s University,
and sustained clinical improvement. Kingston, Ontario, Canada (Kirchhof);
Child and Family Research Institute,
University of British Columbia,
CONCLUSIONS AND RELEVANCE A short course of cyclosporine was of therapeutic benefit in Vancouver, British Columbia, Canada
the treatment of 2 patients with DIHS. Short courses of cyclosporine in the acute care setting (Dutz).
may be an alternative to longer courses of systemic corticosteroids in the treatment of DIHS. Corresponding Author: Mark
Kirchhof, MD, PhD, Division of
Dermatology, Department of
JAMA Dermatol. doi:10.1001/jamadermatol.2016.2220 Medicine, Queen’s University, 166
Published online July 20, 2016. Brock St, Kingston, ON K7L 5G2,
Canada (mgk2@queensu.ca).

D
rug-induced hypersensitivity syndrome (DIHS), also
known as drug reaction with eosinophilia and sys-
temic symptoms (DRESS) syndrome, is a rare, poten-
tially life-threatening adverse reaction to medication. The
diagnosis of DIHS is based on clinical and biochemical find-
ings. It commonly presents clinically with fever, facial swell-
ing, lymphadenopathy, and a morbilliform eruption.1 Inter-
nal organ involvement can include hepatic, renal, pulmonary,
hematologic, cardiac, and endocrine abnormalities.1 Most of-
ten, DIHS is caused by anticonvulsants, antibiotics, and
allopurinol.2 With an estimated mortality rate up to 10%, the
treatment of DIHS is important.3 Treatment of DIHS involves
withdrawal of treatment with the suspected causative medi-
cation, supportive care, and often systemic corticosteroids. In
this observational case series, 2 patients referred to the der-
matology service of an academic tertiary care hospital and sub-
sequently diagnosed as having DIHS were studied from De-
cember 1, 2013, through July 31, 2014. These 2 patients were
treated with a short course of cyclosporine followed by a quick
resolution of the adverse drug reaction. The findings suggest
that cyclosporine is a potential alternative to the traditional long
course of systemic corticosteroids in the treatment of DIHS.
Report of Cases
Case 1
An inpatient dermatology consultation was requested for a
woman in her 40s with a new-onset skin eruption. She had a
history of paraplegia secondary to a motor vehicle crash,

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 Research Brief Report Cyclosporine for Drug-Induced Hypersensitivity Syndrome

chronic renal dysfunction, and seizure disorder. She was pre-

scribed carbamazepine for her seizure disorder. One week af-
ter starting carbamazepine treatment, she developed erythem-
atous edematous papules and plaques on the forearms and
arms that progressed to involve the chest, back, and proximal
extremities. She subsequently developed significant ery-
thema and swelling of the face and ears. Clinical examination
did not reveal any mucosal involvement. Lymph nodes in the
head and neck area were palpable. The patient experienced re-
spiratory distress with decreased oxygen saturations. The pa-
tient stated that she felt feverish, although she was afebrile.
Blood work revealed elevated creatinine and urea concentra-
tions above the levels of her background renal dysfunction
(Figure 1). Hypereosinophilia was also noted. A skin biopsy
specimen from the right volar forearm revealed spongiotic der-
matitis with lymphoid atypia, which was consistent with a drug
hypersensitivity reaction. On the basis of the clinical find-
ings, the patient was diagnosed as having DIHS, which was con-
firmed using the RegiSCAR criteria for DRESS and DIHS (Table
in the Supplement).4 Carbamazepine was identified as the
likely cause of her DIHS, and the patient stopped taking the
drug. The patient was then prescribed cyclosporine, 100 mg
orally twice daily. The patient improved clinically with de-
creased erythema and swelling. Kidney function and respira-
tory distress also improved. After 7 days, treatment with cy-
closporine was stopped without recurrence of symptoms.
Case 2
The dermatology consultation service was asked to see a pa-
tient in his 30s with a 2-day history of a new eruption. The erup-
tion started on the abdomen and subsequently spread to the
legs, arms, hands, feet, and face. The patient noted signifi-
cant swelling, particularly of the hands, feet, and face, that re-
sulted in the sensation of pain. A review of medications indi-
cated that the patient had started taking minocycline for
folliculitis 13 days before the eruption. Use of minocycline was
stopped at the onset of the eruption. Review of previous blood
Key Points
Question Can prompt short-term treatment with cyclosporine
halt drug-induced hypersensitivity syndrome (DIHS)?
Findings This case series describes 2 patients with DIHS who
were treated with a short course (3-7 days) of cyclosporine within
days of syndrome onset. In both cases, the patients experienced a
rapid and sustained clinical resolution of DIHS.
Meaning The rapid and sustained response in our 2 patients
suggests that cyclosporine may be considered first-line therapy for
the treatment of DIHS.
work revealed elevated aspartate aminotransferase and ala-
nine aminotransferase levels. The patient was febrile the day
after the onset of the eruption with a temperature of 38.2°C.
A possible hypoxic event that led to loss of consciousness was
noted with onset of the eruption. Cutaneous examination re-
vealed erythematous edematous papules that coalesced into
plaques distributed over the face, trunk, and extremities
(Figure 2). Facial and lip edema were seen, but no erosions,
vesicles, or bullae were noted. Enlarged palpable lymph nodes
were noted in the submandibular region. A punch biopsy speci-
men taken from the right arm was consistent with a drug hy-
persensitivity reaction. On the basis of the biopsy, clinical ex-
amination, and medical history, the patient was diagnosed as
having DIHS. Using the RegiSCAR criteria for DRESS and DIHS,
the patient was classified as having a probable case of DIHS
(Table in the Supplement).4 The patient began a 3-day course
of oral cyclosporine at a dose of 5 mg/kg per day divided into
twice-daily dosing or a dose of 175 mg twice daily (Figure 3).
Two days after starting treatment with cyclosporine, his
eruption started to resolve. Blood work after the 3-day
course of cyclosporine revealed normal aspartate amino-
transferase and alanine aminotransferase concentrations,
and his eruption had completely resolved. He had no fur-
ther recurrence of symptoms.

Figure 1. Drug-Induced Hypersensitivity Syndrome (DIHS) Resulting From Carbamazepine Therapy Treated With Short-Course Cyclosporine

50 5000 3.0 5000

4500 4500
Urea 2.5 Creatinine
40 Eosinophils 4000 Eosinophils 4000
3500 3500
Creatinine, mg/dL

2.0
Eosinophils, µL
Eosinophils, µl
Urea, mg/dL

30 3000 3000
2500 1.5 2500
20 2000 2000
1.0
1500 1500
10 1000 1000
0.5
500 500
0 0 0 0

1 7 14 21 28 35 42 49 56 63 1 7 14 21 28 35 42 49 56 63
Time, d Time, d

Urea and creatinine levels superimposed on eosinophil counts followed
chronologically from the initiation of carbamazepine treatment. Elevations in
creatinine, urea, and eosinophil levels were noted at approximately day 7 with
onset of DIHS. Subsequent treatment with cyclosporine and withdrawal of use
of carbamazepine resulted in an immediate decrease in creatinine, urea, and
eosinophil levels. Creatinine, urea, and eosinophil levels continued to decrease
during the next month. To convert creatinine to micromoles per liter, multiply
by 88.4; urea to millimoles per liter, multiply by 0.35; and eosinophils to ×109/L,
multiply by 0.001.

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 Cyclosporine for Drug-Induced Hypersensitivity Syndrome
Figure 2. Clinical Image of Patient 2 Showing Morbilliform Eruption on
the Left Thigh
Discussion
The pathogenesis of DIHS has not been fully elucidated.1 Some
of the proposed pathogenic mechanisms include altered drug
metabolism, immune activation, and viral reactivation. Poly-
morphisms in drug detoxification enzymes can result in the
accumulation of toxic drug metabolites.5 These toxic drug me-
tabolites may interact with cellular proteins, resulting in an im-
mune attack. The immune system is believed to play a cen-
tral role in the pathogenesis of DIHS.6 It is well established that
certain HLA haplotypes predispose patients to DIHS.7 These
HLA molecules interact with drug metabolites and are ulti-
mately presented to T cells, resulting in T-cell activation. Be-
cause cyclosporine targets T cells specifically by down-
regulating activation of nuclear factor of activated T cells, it
follows that this might be an appropriate medication to use in
the treatment of DIHS. Reactivation of herpesviruses may also
participate in the pathogenesis of DIHS. It is hypothesized that
T-cell activation may stimulate reactivation and replication of
dormant herpesviruses within immune cells. We speculate that
rapid inhibition of T-cell activation may also inhibit this pro-
posed reactivation.
Treatment of DIHS primarily involves removal of the sus-
pected medication and the use of supportive care, including skin
care and dressings, fluid replacement, correction of electro-
lyte abnormalities, and nutritional support.8 The use of sys-
temic corticosteroids is the most widely used and accepted sys-
temic therapy for DIHS.2,3,8 Patients generally respond well to
corticosteroid therapy, although some cases require alterna-
tives treatments, such as intravenous immunoglobulin, cyclo-
phosphamide, mycophenolate mofetil, rituximab, or
cyclosporine.9 However, the adverse effects of systemic corti-
costeroids can be severe and include increased risk of diabe-
tes, glaucoma and cataracts, osteoporosis, peptic ulcers, osteo-
ARTICLE INFORMATION Published Online: July 20, 2016.
Accepted for Publication: May 22, 2016. doi:10.1001/jamadermatol.2016.2220.
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Brief Report Research
Figure 3. Chronologic Aspartate Aminotransferase (AST) and Alanine
Aminotransferase (ALT) Levels of Patient 2
120
AST
100 ALT
Component, U/L
80
60
40
20
0
Day 13 Day 15 Day 18
Days After Initiation of Minocycline
Benadryl
epinephrine Cyclosporine
Minocycline
Clinical disease
Day 1 Day 13 Day 14 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20
Associated treatment and clinical course are indicated below the figure.
necrosis, and infection. In a retrospective study,8 the use of
systemic corticosteroids was associated with relapse, viral re-
activation, and sepsis compared with topical corticosteroids.
To our knowledge, only 4 cases of cyclosporine treat-
ment for DIHS have been reported.10-13 The first report of cy-
closporine use for DIHS was in a 37-year-old woman who de-
veloped a reaction to phenytoin.10 She was initially treated with
a long tapering course of prednisone, but after 9 months she
had a recurrence of DIHS symptoms and was subsequently
treated with 6 months of 4 mg/kg of cyclosporine daily to good
effect. The second previously reported case involved a pa-
tient with vancomycin-induced DIHS initially treated with cor-
ticosteroids for approximately 2 weeks without any improve-
ment followed by a 5-day course of 100 mg twice daily of
cyclosporine with subsequent clinical resolution.11 The third
and fourth case reports involved patients with DIHS who were
also initially treated with systemic corticosteroids but whose
conditions continued to worsen.12,13 Subsequent treatment
with cyclosporine and other immunosuppressive medica-
tions did not result in clinical resolution, and in 1 of the cases,
the patient died of cardiac-related complications of DIHS.
Conclusions
Although the use of cyclosporine was successful in only 2 of 4
cases previously reported, the rapid and successful response
in our 2 patients suggests that cyclosporine could be consid-
ered as first-line therapy, particularly in patients with con-
cerns about using longer courses of systemic corticosteroids.
Author Contributions: Drs Kirchhof and Dutz had
full access to all the data in the study and take
(Reprinted) JAMA Dermatology Published online July 20, 2016 E3
 Research Brief Report
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data:
Kirchhof, Wong.
Drafting of the manuscript: Kirchhof, Wong.
Critical revision of the manuscript for important
intellectual content: All authors.
Administrative, technical, or material support:
Kirchhof, Wong.
Study supervision: Wong, Dutz.
Conflict of Interest Disclosures: None reported.
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