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Dermatology Online Journal

Title
The use of cyclosporine for Stevens-Johnson syndrome-toxic epidermal necrolysis spectrum
at the University of Louisville: A case series and literature review

Permalink
https://escholarship.org/uc/item/6d56n4j8

Journal
Dermatology Online Journal, 24(1)

Authors
Conner, Clayton D
McKenzie, Emily
Owen, Cindy E

Publication Date
2018

License
CC BY-NC-ND 4.0

Peer reviewed

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University of California
 Volume 24 Number 1 | January 2018
Dermatology Online Journal || Case Report 24 (1): 4

The use of cyclosporine for Stevens-Johnson syndrome-toxic

epidermal necrolysis spectrum at the University of Louisville:
A case series and literature review
Clayton D Conner MSc, Emily McKenzie MD, Cindy E Owen MD, Jeffrey P Callen MD
Affiliations: Division of Dermatology, University of Louisville School of Medicine, Louisville, Kentucky
Corresponding Author: Cindy E. Owen MD, Division of Dermatology, University of Louisville School of Medicine, 3810 Springhurst Boulevard,
Suite 200, Louisville, KY 40241, Tel: [email protected]

Abstract Keywords: Stevens-Johnson syndrome, SJS, toxic

epidermal necrolysis, TEN, cyclosporine, re-
Introduction: Cyclosporine therapy for Stevens- epithelialization, SCORTEN
Johnson syndrome-toxic epidermal necrolysis (SJS-
TEN) was first reported in the literature by Renfro et
al. in 1989. Herein we report an additional 4 cases of Introduction
SJS-TEN treated with cyclosporine. Stevens-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) represent a spectrum of disease and
Methods: Case information was collected retroactively are considered severe cutaneous adverse reactions
at the University of Louisville Hospital in Louisville, (SCARs). SJS/TEN eruptions begin as purpuric macules
KY. All cases had a diagnosis of SJS or TEN by a evolving over the course of hours to days into tender,
dermatologist. All patients were ≥18 years of age and flaccid blisters first appearing on the trunk then
treated with cyclosporine during their admission. spreading to the neck, face, upper arms, palms, and
soles. Buccal, ocular, and genital mucosae are involved
Results: Three of four patients re-epithelialized within in 90% of patients. Respiratory and gastrointestinal
an average of 3.67 days of starting 3-4 mg/kg/day of mucosa involvement is less common. The distinction
cyclosporine. One patient passed away, likely due to between SJS and TEN is based on the amount of body
advanced endometrial cancer. surface area involved. Grade 1 (SJS) is defined as
<10% mucosal erosion and epidermal detachment.
Discussion: We provide a review of the literature Grade 2 (Overlap SJS/TEN) exhibits 10-30%
on cyclosporine use for SJS/TEN, including various epidermal detachment. Grade 3 (TEN) demonstrates
outcome measures — stabilization (cessation of new >30% epidermal detachment. SJS and TEN are most
lesions), time to re-epithelialization, mortality rate, commonly caused by medications (50% and 95%,
and hospital length of stay and, where available, respectively). Among the highest risk medications are
comparison to other systemic agents. nevirapine, lamotrigine, carbamazepine, phenytoin,
phenobarbital, co-trimoxazole, other anti-infective
Conclusion: The outcomes appear to be consistent sulfonamides, sulfasalazine, allopurinol, and oxicam
with rapid re-epithelialization and low mortality as NSAIDs [1]. Due to the rarity of SJS and TEN (annual
seen in many previous reports. Treating SJS-TEN with incidence of 1.2-6.0 and 0.4-1.2 per million persons,
systemic agents including cyclosporine will remain respectively), there are few randomized controlled
controversial because the vast majority of data trials evaluating treatment [2]. Mortality risk can be
comes from case reports, case series, or small open predicted using the SCORTEN scoring system, first
prospective trials. described by Bastuji-Garin et al. as seven binary
parameters calculated on days 1 and 3 of admission
[3]. It has been shown by Cartotto et al. to be a good

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prognostic tool in patients throughout the SJS-TEN and received a diagnosis of SJS with a SCORTEN
spectrum, especially in those being treated in a burn of 1. She was promptly started on 3 mg/kg/day of
center [4]. cyclosporine divided twice daily for three days with
re-epithelialization occurring on day 4 of therapy.
After discontinuing the potentially inciting agent, While hospitalized, she experienced no adverse
management typically consists of supportive care in events, and the SJS eventually resolved.
an intensive care or burn unit, as fluid and electrolyte
loss can be a significant concern. The use of systemic Case #2
agents is debatable as there is only retrospective The patient was a 77-year-old African-American
data regarding their efficacy, with the exception woman with a past medical history of asthma, stroke,
of one randomized control trial demonstrating hyperlipidemia, hypertension, hypothyroidism,
the ineffectiveness of thalidomide in SJS/TEN [21]. prediabetes, and shingles, and a recent diagnosis
Cyclosporine has been proposed as a treatment based of endometrial cancer. Approximately 6 hours
on the recognition of granulysin as a key player in the after receiving IV contrast for a staging CT scan at
apoptosis observed in TEN [9, 10]. As a calcineurin an outside hospital, she developed flesh colored
inhibitor, cyclosporine impairs interleukin-2 (IL- papules on her face and arms with surrounding
2), tumor necrosis factor (TNF), IL-3, IL-4, CD40L, hyperpigmentation. Over the next 24 hours, swelling
interferon-gamma, and granulocyte-macrophage developed in her hands, face, lips, and tongue,
colony-stimulating factor (GM-CSF) transcription, and the papules on her face and arms evolved into
thus reducing T cell proliferation, which could explain painful bullae. She was admitted to the hospital and
its salutary effect. As with any medical intervention started on IV prednisone, which she received until
in SJS-TEN, the therapeutic window is narrow. Renal being transferred to ULH on hospital day 10. Upon
insufficiency remains the most common reason for examination, she received a diagnosis of TEN with
premature discontinuation, as acute renal failure a SCORTEN of 5. She was quickly started on 3 mg/
occurs in up to 20% of all SJS-TEN cases. It is our aim kg/day of cyclosporine divided twice daily, but only
that this series of four cases and review of the current for one day. Due to her worsening condition, the
literature will shed additional light on better treating decision was made to transition to comfort care only.
this devastating disease. Lifesaving care was subsequently withdrawn, and
she expired.
Methods
Case information was collected retroactively at the Case #3
University of Louisville Hospital (ULH) in Louisville, KY. The patient was a 62-year-old Caucasian male with a
All cases had a clinical or histopathological diagnosis past medical history of atrial fibrillation, congestive
of SJS or TEN by a dermatologist. All patients were heart failure, hypertension, and chronic kidney
≥18 years of age and treated with cyclosporine disease secondary to glomerulonephritis. After
during their admission. Due to the limited size of this taking trimethoprim-sulfamethoxazole for 98 days,
case series, the project was considered institutional he developed erythematous macules and patches
review board (IRB) exempt. with desquamation on his arms, abdomen, and
groin, as well as erosions with hemorrhagic crusting
Results on his face and oral mucosa. These mucocutaneous
findings worsened during the 10 days leading up
Case #1 to his presentation to an outside hospital, where he
The patient was a 23-year-old Caucasian woman spent 5 days before being transferred to ULH. He
being treated for schizophrenia at a psychiatric received a diagnosis of TEN, a SCORTEN of 4, and
hospital. After starting carbamazepine 20 days prior, began taking 3 mg/kg/day of cyclosporine divided
she developed erythematous papules, vesicles, twice daily for four days. He re-epithelialized on day
and bullae on her face, conjunctival injection, and 3 of therapy, experienced no adverse events, and the
oral erosions. Her conditioned worsened over the TEN eventually resolved.
next 7 days, upon which she presented to ULH

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Case #4 consisting of 29 patients. By day 3 of therapy, 62% of

The patient was a 31-year-old African-American patients had stabilized with cyclosporine compared
male with no significant past medical history to 35% with IVIG. Despite SCORTEN predicting 2.75
taking trimethoprim-sulfamethoxazole. On day 5 of deaths, there were no mortalities. The average re-
therapy, he developed tender erythematous plaques epithelialization time was 12.57 days [16]. Three
on his back, erosions in his groin, perioral crusting, of the 29 patients experienced side effects that
and conjunctival injection. He presented to ULH prompted discontinuing therapy, including acute
4 days later and received a diagnosis of SJS with a hallucinations from suspected reversible posterior
SCORTEN of 1. He was started on 3 mg/kg/day of leukoencephalopathy, transient neutropenia, and
cyclosporine divided twice daily for five days with nosocomial pneumopathy. Two patients were
re-epithelialization occurring on day 4. During the tapered earlier than scheduled due to mild renal
hospital course, the patient experienced no adverse insufficiency. In a 2011 case series of 4 patients, Reese
events, and the SJS eventually resolved. et al. reported no further progression after starting
cyclosporine and a mortality rate of 0 of 4 patients
Discussion [17]. Later that year, Carmona et al. published a case
To the best of our knowledge, cyclosporine therapy series of 3 patients that stabilized within 48 hours of
for SJS-TEN has been reported in 12 previous starting therapy, re-epithelialized within 11.67 days
publications involving 183 patients, beginning with on average, and experienced no mortalities [18]. In
Renfro et al. in 1989 [11]. Authors have included a an open uncontrolled study of 17 patients, Singh
variety of outcome measures, namely stabilization et al. compared retrospective data of those treated
(cessation of new lesions), time to re-epithelialization, with cyclosporine versus corticosteroids. Patients
mortality rate, and hospital length of stay. For a more treated with cyclosporine stabilized in 3.18 days on
succinct review of the reports, please refer to Table 3. average and 4.75 days with corticosteroids. Complete
In Renfro’s unprecedented report, a patient stabilized re-epithelialization occurred in 14.54 days with
and re-epithelialized within 3 days of starting cyclosporine and 23.0 days with corticosteroids. The
cyclosporine and had a hospital stay of 10 days [11]. mortality rate was 0 of 11 with cyclosporine and 2 of
Seven years later in 1996, Sullivan et al. published 6 with corticosteroids. Hospital stay was 18.09 days
a patient that stabilized within 24 hours of starting with cyclosporine and 26 days with corticosteroids
cyclosporine, achieved complete re-epithelialization [19]. In 2014, Kirchhof et al. published a retrospective
in 2 weeks, and had a hospital stay of 72 days [12]. review of 64 patients treated conservatively (n=12),
In another case report by Jarrett et al., a patient with IVIg (n=35), with cyclosporine (n=15), and with
stabilized within hours of starting cyclosporine both IVIg and cyclosporine (n=2). Mortality rates
and achieved complete re-epithelialization within were 1 of 13 with cyclosporine (despite 2.4 predicted
12 days [13]. In 2000, Arévalo et al. published the with SCORTEN) compared to 11 of 37 with IVIg (only
first case series comparing cyclosporine (n=11) to 7.4 predicted with SCORTEN). This translated to a
cyclophosphamide and corticosteroids (n=6). Their more favorable standardized mortality ratio (SMR =
group reported an average re-epithelialization time sum of observed deaths/sum of expected deaths) of
of 12.0 days with cyclosporine compared to 17.6 0.42 with cyclosporine versus 1.43 with IVIg [8]. Most
days with cyclophosphamide and corticosteroids. A recently, Lee et al. published a retrospective cohort
more favorable mortality rate with cyclosporine was of 44 patients treated with either cyclosporine
also of note, which was 0 of 11 compared to 3 of 6 (n=24) or supportive care only (n=20). Treatment
[7]. Hashim et al. describes a patient that stabilized with cyclosporine showed a mortality rate of 3 of
within 24 hours of beginning therapy and completely 24 despite 7.18 predicted with SCORTEN, which
re-epithelialized within 72 hours [14]. A similar report compared to 6 of 20 with supportive care only (5.90
by Aihara et al. recounts a patient with TEN that predicted). This rendered an auspicious SMR of 0.42
stabilized within 24 hours of starting cyclosporine, with cyclosporine versus 1.02 with supportive care
had completely re-epithelialized in 14 days, and only. Adjusting for SCORTEN, Charlson comorbidity
had a hospital stay of 43 days [15]. In 2010, Valeyrie- index, and days of delay to admission, risk ratio for
Allanore et al. published the first open phase II trial death with cyclosporine versus supportive care was

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Table 1. SCORTEN scoring system for predicting patient outcome in TEN [3]

SCORTEN Parameters Points

>10% epidermal detachment 0 or 1

Age >40 years 0 or 1

History of malignancy 0 or 1

Heart rate >120 BPM 0 or 1

Urea >10 mmol/L 0 or 1

Glucose >14 mmol/L 0 or 1

Bicarbonate <20 mmol/L 0 or 1

Total 0-7

SCORTEN Total Points Predicted Mortality Rate (%)

0-1 3.2

2 12.1

3 35.3

4 58.3

≥5 90.0

Table 2. Patient demographics and clinical features

Case #1 Case #2 Case #3 Case #4

Sex Female Female Male Male

Age 23 years 77 years 62 years 31 years

Race/ethnicity White Black White Black

Comorbidities Endometrial cancer

Diagnosis SJS TEN TEN SJS

Etiology Carbamazepine IV contrast TMP/SMX TMP/SMX

Erythematous mac-
ules and patches with Tender erythematous
Erythematous papules,
desquamation on arms, plaques on back; ero-
Description of vesicles, and bullae on
Bullae on face and arms abdomen, and groin; sions in groin; perioral
lesions face; conjunctival injec-
erosions with hemor- crusting; conjunctival
tion; oral erosions
rhagic crusting on face injection
and oral mucosa
SCORTEN 1 5 4 1
Day at
2 10 5 3
presentation
Dose of 3 mg/kg/day (given in 3 mg/kg/day (given in 3 mg/kg/day (given in 3 mg/kg/day (given in
cyclosporine divided doses BID) divided doses BID) divided doses BID) divided doses BID)
Length of
3 days 1 day 4 days 5 days
treatment

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Case #1 Case #2 Case #3 Case #4

Time to re-
4 days N/A 3 days 4 days
epithelialization
Adverse events None Care Withdrawn None None

Outcome Resolved Deceased Resolved Resolved

Miscellaneous 10 days of IV prednisone Transfer from outside
information prior to arrival facility

Table 3. Chronologic summary of cyclosporine usage in SJS-TEN spectrum.

# of
Authors Year Dx Etiology Treatment(s) Outcome(s) Complication(s)
Patients
Stabilized and
re-epithelialized
Renfro et al. [11]
1989 1 TEN Phenytoin Cyclosporine within 3 days. None
[PMID: 2777442]
Hospital stay of
10 days.
1. IV hydrocortisone
300mg Stabilized within
24 hours. Com-
2. dexamethasone
Sullivan et al. [12] plete re-epithe-
1996 1 TEN Lamotrigine 4mg QID x 3 days None
[PMID: 8961591] lialization in 2
3. IV cyclosporine weeks. Hospital
4.5 mg/kg/day x 16 stay of 72 days.
days
Stabilized within
hours. Complete
Jarrett et al. [13] Carbamazap- IV cyclosporine
1997 1 TEN re-epithelializa- None
[PMID: 9536553] ine 5mg/kg
tion within 12
days.
Allopurinol
(2),
NSAID (2),
Metamizol (1), Complete re-ep-
Ranitidine (1), ithelialization
within 12.0 days
Corticoste- Oral cyclosporine
vs. 17.6 days
roids (3). 3mg/kg/day divid-
with cyclophos-
Arévalo et Tetrabamate ed twice daily (11)
phamide and
al. [7] [PMID: 2000 17 TEN (1), vs. cyclophospha- None
corticosteroids.
10744287] Septrim (1), mide 150 mg Q12H
Mortality rate 0
and corticosteroids
Phenytoin (1), of 11 vs. 3 of 6
(6)
Carbamaze- with cyclophos-
pine (1), phamide and
Aspirin (1), corticosteroids.
Paracetamol
(1), Vitamin
B (1)
Stabilized
Hashim et al. Cyclosporine 2 mg/ within 24 hours.
Overlap
[14] [PMID: 2003 1 Lamotrigine kg/day divided Completely
SJS/TEN
15040495] twice daily x 4 days re-epithelialized
within 72 hours.

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# of
Authors Year Dx Etiology Treatment(s) Outcome(s) Complication(s)
Patients
1. Oral predniso-
lone 40mg daily Stabilized
within 24 hours.
2. IV ulinatatin
Aihara et al. Completely
[15] [PMID: 2007 1 TEN Unknown 3. IV cyclosporine re-epithelialized
17875095] 1 mg/kg/day with within 14 days.
methylpredniso- Hospital stay of
lone (30 mg/kg/ 43 days.
day) x 3 days
Nevirapine
62% of patients Acute hallucinations
(4), Lamo-
stabilized at day (suspected reversible
trigine (3),
3 vs. 35% with posterior leukoen-
SJS (10) Sulfonamides IVIG. Mortality cephalopathy) (n=1),
Valeyrie-Allanore (3), Amifostine
SJS/TEN Oral Cyclosporine 3 rate 0 of 29 Transient neutropenia
et al. [16] [PMID: 2010 29 (3), Carba-
(12) mg/kg x 10 days (2.75 predicted (n=1), Severe infection
20500799] mazepine (2),
TEN (7) Quinolones with SCORTEN). (nosocomial pneu-
Re-epithelial- mopathy) (n=1), mild
(2), Allo-
ization within renal insufficiency
purinol (1),
12.57 days (n=2)
Oxicam (1)
TMP-SMX (2)
No further
Reese et al. Lamotrigine Cyclosporine 5 mg/
progression in
[17] [PMID: 2011 4 SJS/TEN (1) kg/day divided
any patients. No
21323097] Acetamino- twice daily
deaths.
phen (1)
Stabilized
Allopurinol (2) within 48 hours.
Carmona et Cyclosporine 3 mg/
Amoxicil- Re-epitheliali-
al. [18] [PMID: 2011 3 TEN kg/day divided
lin-clavulanic twice daily zed within 11.67
21215491]
acid (1) days. Mortality
rate 0 of 3.
Stabilized within
3.18 days vs.
Ofloxacin (1), 4.75 days with
Dilantin (2), corticosteroids.
Norfloxacin Complete
(1), Cyclosporine 3 mg/ re-epitheliali-
SJS (8), Ciprofloxacin kg/day divided zation within
Singh et al. Overlap (1), three times daily 14.54 days vs.
[19] [PMID: 2013 17 SJS/TEN Ibuprofen (3), (open, uncontrolled 23.0 days with
23974585] (4), TEN trial) vs. corticoste- corticosteroids.
Tinidazole (1),
(5) roids (retrospective Mortality rate 0
Dilantin (1), data) of 11 vs. 2 of 6
Carbamaze- with corticoste-
pine (1), roids. Hospital
Unknown (1) stay 18.09 days
vs. 26 days with
corticosteroids.

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# of
Authors Year Dx Etiology Treatment(s) Outcome(s) Complication(s)
Patients
12 patients treated
conservatively
35 patients: IVIg Mortality rate
(average 1mg/kg/ 1 of 13 (2.4
SJS (28),
day x 3 days) predicted with
Overlap
Kirchhof et SCORTEN) vs. 11
SJS/TEN 15 patients: Cyclo-
al. [8] [PMID: 2014 64 Not reported of 37 with IVIg
(19), sporine (average
25087214] (7.4 predicted
TEN 3-5 mg/kg/d x 7 with SCORTEN).
(17) days) SMR 0.42 vs.
2 patients: both 1.43 with IVIg.
IVIg and Cyclospo-
rine
Mortality rate
3 of 24 (7.18
24 patients treated predicted with
with cyclosporine, SCORTEN) vs.
Creteil: 3 mg/ 6 of 20 with
kg/d for 10 days, supportive
followed by 2 mg/ care only (5.90
kg/d for 10 days, predicted with
SJS (16)
and lastly 1 mg/ SCORTEN). SMR
Overlap
Lee et al. kg/d for 10 days; of 0.42 vs. 1.02
SJS/TEN
[20] [PMID: 2017 44 Not reported administered orally with supportive
(12),
27717620] or via nasogastric care only. Risk
TEN
tubes; any prior ratio for death
(16)
immunomodulat- with cyclospo-
ing agents were rine vs. support-
stopped ive care was
0.49. Length of
20 patients treated hospital stay 20
supportively days vs. 14 days
with supportive
care only.

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epidermal necrolysis. J Invest Dermatol. 2000 Aug;115(2):149-53.

0.49. Interestingly, the average length of hospital stay [PMID: 10951229].
was 20 days with cyclosporine versus 14 days with 4. Cartotto R, Mayich M, Nickerson D, Gomez M. SCORTEN accurately
supportive care only [20]. The patients in our case predicts mortality among toxic epidermal necrolysis patients
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hospital length of stay with cyclosporine therapy. e1-16; quiz 203-4. [PMID: 23866879].
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or supportive care only, cyclosporine appears to 12. Sullivan JR, Watson A. Lamotrigine-induced toxic epidermal
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Brun-Buisson C, Revuz J. Randomised comparison of thalidomide

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