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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 matology service of an academic tertiary care hospital and sub-
known as drug reaction with eosinophilia and sys- sequently diagnosed as having DIHS were studied from De-
temic symptoms (DRESS) syndrome, is a rare, poten- cember 1, 2013, through July 31, 2014. These 2 patients were
tially life-threatening adverse reaction to medication. The treated with a short course of cyclosporine followed by a quick
diagnosis of DIHS is based on clinical and biochemical find- resolution of the adverse drug reaction. The findings suggest
ings. It commonly presents clinically with fever, facial swell- that cyclosporine is a potential alternative to the traditional long
ing, lymphadenopathy, and a morbilliform eruption.1 Inter- course of systemic corticosteroids in the treatment of DIHS.
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
Report of Cases
treatment of DIHS is important.3 Treatment of DIHS involves Case 1
withdrawal of treatment with the suspected causative medi- An inpatient dermatology consultation was requested for a
cation, supportive care, and often systemic corticosteroids. In woman in her 40s with a new-onset skin eruption. She had a
this observational case series, 2 patients referred to the der- 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- Key Points
ter starting carbamazepine treatment, she developed erythem-
Question Can prompt short-term treatment with cyclosporine
atous edematous papules and plaques on the forearms and halt drug-induced hypersensitivity syndrome (DIHS)?
arms that progressed to involve the chest, back, and proximal
Findings This case series describes 2 patients with DIHS who
extremities. She subsequently developed significant ery-
were treated with a short course (3-7 days) of cyclosporine within
thema and swelling of the face and ears. Clinical examination
days of syndrome onset. In both cases, the patients experienced a
did not reveal any mucosal involvement. Lymph nodes in the rapid and sustained clinical resolution of DIHS.
head and neck area were palpable. The patient experienced re-
Meaning The rapid and sustained response in our 2 patients
spiratory distress with decreased oxygen saturations. The pa-
suggests that cyclosporine may be considered first-line therapy for
tient stated that she felt feverish, although she was afebrile.
the treatment of DIHS.
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 work revealed elevated aspartate aminotransferase and ala-
specimen from the right volar forearm revealed spongiotic der- nine aminotransferase levels. The patient was febrile the day
matitis with lymphoid atypia, which was consistent with a drug after the onset of the eruption with a temperature of 38.2°C.
hypersensitivity reaction. On the basis of the clinical find- A possible hypoxic event that led to loss of consciousness was
ings, the patient was diagnosed as having DIHS, which was con- noted with onset of the eruption. Cutaneous examination re-
firmed using the RegiSCAR criteria for DRESS and DIHS (Table vealed erythematous edematous papules that coalesced into
in the Supplement).4 Carbamazepine was identified as the plaques distributed over the face, trunk, and extremities
likely cause of her DIHS, and the patient stopped taking the (Figure 2). Facial and lip edema were seen, but no erosions,
drug. The patient was then prescribed cyclosporine, 100 mg vesicles, or bullae were noted. Enlarged palpable lymph nodes
orally twice daily. The patient improved clinically with de- were noted in the submandibular region. A punch biopsy speci-
creased erythema and swelling. Kidney function and respira- men taken from the right arm was consistent with a drug hy-
tory distress also improved. After 7 days, treatment with cy- persensitivity reaction. On the basis of the biopsy, clinical ex-
closporine was stopped without recurrence of symptoms. amination, and medical history, the patient was diagnosed as
having DIHS. Using the RegiSCAR criteria for DRESS and DIHS,
Case 2 the patient was classified as having a probable case of DIHS
The dermatology consultation service was asked to see a pa- (Table in the Supplement).4 The patient began a 3-day course
tient in his 30s with a 2-day history of a new eruption. The erup- of oral cyclosporine at a dose of 5 mg/kg per day divided into
tion started on the abdomen and subsequently spread to the twice-daily dosing or a dose of 175 mg twice daily (Figure 3).
legs, arms, hands, feet, and face. The patient noted signifi- Two days after starting treatment with cyclosporine, his
cant swelling, particularly of the hands, feet, and face, that re- eruption started to resolve. Blood work after the 3-day
sulted in the sensation of pain. A review of medications indi- course of cyclosporine revealed normal aspartate amino-
cated that the patient had started taking minocycline for transferase and alanine aminotransferase concentrations,
folliculitis 13 days before the eruption. Use of minocycline was and his eruption had completely resolved. He had no fur-
stopped at the onset of the eruption. Review of previous blood 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 eosinophil levels. Creatinine, urea, and eosinophil levels continued to decrease
chronologically from the initiation of carbamazepine treatment. Elevations in during the next month. To convert creatinine to micromoles per liter, multiply
creatinine, urea, and eosinophil levels were noted at approximately day 7 with by 88.4; urea to millimoles per liter, multiply by 0.35; and eosinophils to ×109/L,
onset of DIHS. Subsequent treatment with cyclosporine and withdrawal of use multiply by 0.001.
of carbamazepine resulted in an immediate decrease in creatinine, urea, and

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Cyclosporine for Drug-Induced Hypersensitivity Syndrome Brief Report Research

Figure 2. Clinical Image of Patient 2 Showing Morbilliform Eruption on Figure 3. Chronologic Aspartate Aminotransferase (AST) and Alanine
the Left Thigh 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

Discussion
Day 1 Day 13 Day 14 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20

The pathogenesis of DIHS has not been fully elucidated.1 Some


Associated treatment and clinical course are indicated below the figure.
of the proposed pathogenic mechanisms include altered drug
metabolism, immune activation, and viral reactivation. Poly- necrosis, and infection. In a retrospective study,8 the use of
morphisms in drug detoxification enzymes can result in the systemic corticosteroids was associated with relapse, viral re-
accumulation of toxic drug metabolites.5 These toxic drug me- activation, and sepsis compared with topical corticosteroids.
tabolites may interact with cellular proteins, resulting in an im- To our knowledge, only 4 cases of cyclosporine treat-
mune attack. The immune system is believed to play a cen- ment for DIHS have been reported.10-13 The first report of cy-
tral role in the pathogenesis of DIHS.6 It is well established that closporine use for DIHS was in a 37-year-old woman who de-
certain HLA haplotypes predispose patients to DIHS.7 These veloped a reaction to phenytoin.10 She was initially treated with
HLA molecules interact with drug metabolites and are ulti- a long tapering course of prednisone, but after 9 months she
mately presented to T cells, resulting in T-cell activation. Be- had a recurrence of DIHS symptoms and was subsequently
cause cyclosporine targets T cells specifically by down- treated with 6 months of 4 mg/kg of cyclosporine daily to good
regulating activation of nuclear factor of activated T cells, it effect. The second previously reported case involved a pa-
follows that this might be an appropriate medication to use in tient with vancomycin-induced DIHS initially treated with cor-
the treatment of DIHS. Reactivation of herpesviruses may also ticosteroids for approximately 2 weeks without any improve-
participate in the pathogenesis of DIHS. It is hypothesized that ment followed by a 5-day course of 100 mg twice daily of
T-cell activation may stimulate reactivation and replication of cyclosporine with subsequent clinical resolution.11 The third
dormant herpesviruses within immune cells. We speculate that and fourth case reports involved patients with DIHS who were
rapid inhibition of T-cell activation may also inhibit this pro- also initially treated with systemic corticosteroids but whose
posed reactivation. conditions continued to worsen.12,13 Subsequent treatment
Treatment of DIHS primarily involves removal of the sus- with cyclosporine and other immunosuppressive medica-
pected medication and the use of supportive care, including skin tions did not result in clinical resolution, and in 1 of the cases,
care and dressings, fluid replacement, correction of electro- the patient died of cardiac-related complications of DIHS.
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-
Conclusions
tives treatments, such as intravenous immunoglobulin, cyclo- Although the use of cyclosporine was successful in only 2 of 4
phosphamide, mycophenolate mofetil, rituximab, or cases previously reported, the rapid and successful response
cyclosporine.9 However, the adverse effects of systemic corti- in our 2 patients suggests that cyclosporine could be consid-
costeroids can be severe and include increased risk of diabe- ered as first-line therapy, particularly in patients with con-
tes, glaucoma and cataracts, osteoporosis, peptic ulcers, osteo- cerns about using longer courses of systemic corticosteroids.

ARTICLE INFORMATION Published Online: July 20, 2016. Author Contributions: Drs Kirchhof and Dutz had
Accepted for Publication: May 22, 2016. doi:10.1001/jamadermatol.2016.2220. full access to all the data in the study and take

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Research Brief Report Cyclosporine for Drug-Induced Hypersensitivity Syndrome

responsibility for the integrity of the data and the a study of 30 cases in Taiwan. J Eur Acad Dermatol a retrospective study of 38 cases. J Am Acad
accuracy of the data analysis. Venereol. 2008;22(9):1044-1049. Dermatol. 2015;72(2):246-252.
Study concept and design: All authors. 4. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, 9. Husain Z, Reddy BY, Schwartz RA. DRESS
Acquisition, analysis, or interpretation of data: et al. Variability in the clinical pattern of cutaneous syndrome, part II: management and therapeutics.
Kirchhof, Wong. side-effects of drugs with systemic symptoms: does J Am Acad Dermatol. 2013;68(5):709.e1-709.e9.
Drafting of the manuscript: Kirchhof, Wong. a DRESS syndrome really exist? Br J Dermatol.
Critical revision of the manuscript for important 10. Harman KE, Morris SD, Higgins EM. Persistent
2007;156(3):609-611. anticonvulsant hypersensitivity syndrome
intellectual content: All authors.
Administrative, technical, or material support: 5. Wolkenstein P, Charue D, Laurent P, Revuz J, responding to ciclosporin. Clin Exp Dermatol. 2003;
Kirchhof, Wong. Roujeau JC, Bagot M. Metabolic predisposition to 28(4):364-365.
Study supervision: Wong, Dutz. cutaneous adverse drug reactions: role in toxic 11. Zuliani E, Zwahlen H, Gilliet F, Marone C.
epidermal necrolysis caused by sulfonamides and Vancomycin-induced hypersensitivity reaction with
Conflict of Interest Disclosures: None reported. anticonvulsants. Arch Dermatol. 1995;131(5):544-551. acute renal failure: resolution following
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