Pediatric Dermatology Vol. 34 No.

5 540–546, 2017

Successful Use of Cyclosporin A for

Stevens–Johnson Syndrome and Toxic
Epidermal Necrolysis in Three Children
Jessica St. John , M.D., M.P.H., M.B.A.,* Vladimir Ratushny, M.D., Ph.D.,† Kristina J. Liu,
M.D.,† Daniel Q. Bach, M.D., M.P.H.,† Omar Badri, M.D.,† Lia E. Gracey, M.D., Ph.D.,†
Allen W. Ho, M.D., Ph.D.,† Adam B. Raff, M.D., Ph.D.,† Daniel Y. Sugai, M.D.,†
Peter Schalock, M.D.,* and Daniela Kroshinsky, M.D., M.P.H.*
*Department of Dermatology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts,
†Harvard Combined Dermatology Residency, Harvard Medical School, Boston, Massachusetts

Abstract
Background/Objectives: Stevens–Johnson syndrome (SJS) and toxic epi-
dermal necrolysis (TEN) are medical emergencies. Mainstays of treatment
include removal of the offending agent, supportive care, and wound care. The
use of immunosuppressive agents such as corticosteroids and intravenous
immunoglobulin (IVIg) is controversial. Some case reports and small studies
report the successful use of cyclosporin A (CsA) for SJS/TEN in halting disease
progression, fostering reepithelialization, and reducing mortality.
Objective: To report on the efficacy of cyclosporine A in the treatment of SJS/
TEN in three pediatric patients.
Methods: We describe three pediatric patients seen at a tertiary care hospital in
Boston, Massachusetts, diagnosed with SJS/TEN confirmed by skin biopsy who
were successfully treated with CsA with improvements seen in time to cessation
of disease progression or new lesion formation, reepithelialization, and duration
of hospital stay.
Results: The average time cessation of disease progression or new lesion
formation after CsA administration was 2.2 days (range 1.5–3 days) and
average time to remission or reepithelialization was 13 days (range 10–
15 days). The average length of hospital stay was 11.7 days (range 4–19 days).
Conclusions: We describe three pediatric patients treated successfully with
CsA and provide evidence for the use of cyclosporine in children with SJS/TEN.
These results further support previous observations that CsA use for SJS/TEN
produces consistently favorable outcomes. The results in this case series are
limited by their observational nature. Additional trials are needed to evaluate the
safety and efficacy of CsA use in children.

Address correspondence to Daniela Kroshinsky, M.D., M.P.H.,

Department of Dermatology, Massachusetts General Hospital,
55 Fruit Street, Boston, MA 02114, or e-mail: dkroshinsky@mgh.
harvard.edu.

DOI: 10.1111/pde.13236

540 © 2017 Wiley Periodicals, Inc.


Stevens–Johnson syndrome (SJS) and toxic epider-
mal necrolysis (TEN) are rare medical emergencies
characterized by widespread skin necrosis and the risk
of hemodynamic instability and sepsis. Estimated
mortality is 5% for SJS and 30% to 50% for
TEN; mortality is much lower in children (1). Adverse
drug reactions cause the majority of SJS/TEN
cases, although some may be due to infection (e.g.,
Mycoplasma pneumoniae).
Mainstays of treatment for SJS/TEN include
removal of the offending agent, supportive care, and
appropriate wound care. The use of immunosuppres-
sive agents such as corticosteroids and intravenous
immunoglobulin (IV Ig) is controversial. Neither
treatment has an established clinical benefit and there
have been reported associations with greater mortality
(1–3). In contrast, the use of cyclosporine A (CsA) in
SJS/TEN has been associated with cessation of disease
progression or new lesion formation, increased reep-
ithelialization, and reduced mortality (3–5).
There is a paucity of research on the treatment of
pediatric SJS/TEN. One recent meta-analysis found
that children treated with IVIg as compared with
supportive care had significantly better outcomes, but
without a control group for comparison, the observed
improved prognosis may be attributable to the overall
higher recovery rates seen in children than in adults
with SJS/TEN (2). In this case series we describe three
children treated successfully with CsA and provide
evidence for the use of CsA to treat SJS/TEN.
CASE REPORTS
Patient 1
A 17-month-old boy with a recent diagnosis of acute
disseminated encephalomyelitis (ADEM) after a Cox-
sackie infection was treated with IV methylpred-
nisolone 3 mg/kg/day for 5 days followed by IVIg
1 g/kg/day for 2 days at an outside hospital. Elec-
troencephalography showed subclinical seizure activ-
ity and the patient was given IV fosphenytoin and
subsequently transitioned to oral phenytoin 25 mg
twice a day. Eleven days after starting phenytoin, the
patient developed pink macules and papules on his
bilateral cheeks. He was treated with an oral steroid
taper, topical diphenhydramine, and hydrocortisone
for presumed contact dermatitis and continued on
phenytoin. One week later (18 days after starting
phenytoin), he became febrile (102.7°F) and developed
a diffuse, morbilliform eruption. He had received 6 mg
of oral prednisone daily for 6 days before he was
transferred to our emergency department (ED).
St. John et al: Successful Use of CSA for SJS/TEN 541
Upon admission, phenytoin was discontinued and
prednisolone was started at 1.5 mg/kg/day. Complete
blood count (CBC) with differential and liver function
tests (LFTs) were within normal limits except for
aspartate aminotransferase of 125 U/L (normal range
9–80 U/L) and alanine aminotransferase of 68 U/L
(normal range 10–55 U/L). On day 2 he was intubated
because of respiratory distress and transferred to the
pediatric intensive care unit. His phenytoin level was
still therapeutic at 7.0 lg/mL (normal range 5.0–
20.0 lg/mL), despite discontinuation several days
before. On day 3 he developed numerous tense vesicles
and bullae on his chest and abdomen and erythema at
the urethral meatus. Ophthalmology also noted con-
junctival erosions. A biopsy specimen of the upper
chest revealed full-thickness epidermal necrosis con-
sistent with SJS/TEN. Intravenous CsA was initiated
on day 4 at 3 mg/kg/day divided into two doses and
maintained for 7 days.
Progression of the vesicles, bullae, and erosions
continued for 1.5 days after initiation of CsA, involv-
ing approximately 25% of his body surface area (BSA),
but by day 2 of CsA treatment, the lesions stopped
progressing. Over the next 1 to 2 days, dramatic
improvement was noted in the extent of erythema
and erosions. The patient’s superficial conjunctival
erosions were managed with bandage contact lenses
and had nearly resolved 3 days after initiating CsA.
Near-complete reepithelialization was observed by day
10 of treatment and he was discharged to a rehabili-
tation facility on hospital day 19. Three weeks later he
was seen for follow-up in the dermatology clinic with
completely normalized skin. His parents were
instructed to list phenytoin as an allergy.
Patient 2
A healthy 5-year-old boy presented to the ED with a
generalized body rash, conjunctival irritation, painful
lip erosions, and anogenital irritation after taking
acetaminophen the night before in the setting of
cough and fever. He had not taken acetaminophen
before and took no other regular medications. In the
ED, he was given IV fluids and another dose of
acetaminophen. Dermatologic evaluation in the ED
revealed a diffuse morbilliform eruption involving the
torso, extremities, palms, soles, and bilateral cheeks,
with conjunctival injection; serosanguineous erosions
on the lips; a pink, tender patch on the glans penis;
and superficial perianal erosions. A skin biopsy
specimen of the back revealed multifocal epidermal
keratinocyte dyskeratosis consistent with erythema
multiforme or early SJS/TEN. On day 2 of admission
542 Pediatric Dermatology Vol. 34 No. 5 September/October 2017
the patient developed vesicles on the bilateral cheeks,
chin, and right upper arm involving an estimated 15%
of his BSA. Considering the rapid progression of skin
involvement, CsA treatment was initiated at 3 mg/kg/
day divided into two doses and fluocinolone 0.025%
ointment was applied to the skin lesions.
Because of concern for M. pneumoniae infection,
the patient was treated with IV levofloxacin for
5 days, which was discontinued when serologic testing
was negative. An extensive infectious disease exami-
nation was negative for herpes simplex virus 1/2, beta-
hemolytic Streptococcus, parainfluenza virus, influ-
enza A virus, adenovirus, and respiratory syncytial
virus. Serologic testing was positive for Epstein–Barr
virus IgG, indicating a previous, nonactive infection.
The patient had a normal urinalysis and culture.
Lesion formation stopped by day 3 of CsA
administration and he had completely reepithelialized
by day 15. He was discharged from the hospital on
day 12 with acetaminophen as the presumed causative
agent. In total, he was treated with CsA 3 mg/kg for
8 days, followed by 1.5 mg/kg for 7 days, with no
recurrence.
Patient 3
A healthy 8-year-old girl had developed an itchy, pink
eruption on her posterior neck 2 days before presen-
tation. The eruption progressed and she developed a
fever to 102°F. She had no prior medication exposure.
Upon admission, dermatology evaluated her and
found that she had bilateral conjunctival injection
and numerous pink, edematous, targetoid papules
and plaques over her face, neck, torso, and extremities
involving an estimated 15% of her BSA. She was
afebrile, and CBC and complete metabolic panel were
within normal limits. CsA was started at 3 mg/kg/day
divided into twice-daily dosing because of concern
about early SJS/TEN. Serologies for Mycoplasma and
Bartonella were performed. On the second day she
developed involvement of the lips and labia majora,
but new lesion formation stopped within 2 days of
initiating CsA. Her blood work remained within
normal limits, with the exception of mild leukopenia
(2.9 9 103 cells/lL on day 3 of treatment, normal
range 4.5–13.5 9 103 cells/lL), which resolved spon-
taneously.
Upon discharge on hospital day 4, the CsA dose
was decreased to 1 mg/kg/day because of her remark-
able recovery, but within 2 days she began to rapidly
develop new lesions. Her CsA dose was increased to
3 mg/kg/day on day 8, with complete resolution of her
skin findings over the next 7 days. The dosage was
then tapered to 1.5 mg/kg/day for another week, for a
total treatment length of 21 days. Complete reepithe-
lialization occurred after 14 days of CsA. Antibodies
against Bartonella henselae and quintana were nega-
tive. M. pneumoniae IgM antibodies were positive
(IgG negative), although indirect immunofluores-
cence was not confirmatory, and the positive reaction
was thought to be due to inflammation.
DISCUSSION
We describe three children treated successfully with
CsA for SJS/TEN. The average time in delay to
admission was 3.3 days (range 0–8 days) and delay in
diagnosis to treatment was 1.0 day (range 0–2 days).
(See Table 1 for a summary of these cases.) The
average response time after CsA administration was
2.2 days (range 1.5–3 days) and the average time to
remission or reepithelialization was 13 days (range
10–15 days). The average length of hospital stay was
11.7 days (range 4–19 days). Our results support
other reports of successful CsA use for SJS/TEN,
with cessation of disease progression, increased reep-
ithelialization rates, and decreased mortality as
compared with supportive care or other treatment
options (Table 2) (3–5).
The mechanism of action of CsA is critical to
understanding its use in the treatment of SJS/TEN.
SJS/TEN is characterized by widespread keratinocyte
apoptosis initiated by natural killer cells, cytotoxic T-
cells, and tumor necrosis factor alpha (1). CsA inhibits
T-cell activation, preventing T-cells from producing
cytokines critical to the pathogenesis and propagation
of SJS/TEN (6). Thus CsA selectively targets the
immunologic changes in SJS/TEN that propagate
keratinocyte death and prevents apoptosis. CsA does
not affect already-activated and already-released
cytokines (1), accounting for the slight delay in
response time for patients treated with CsA. Once a
response is initiated, the results are dramatic.
The response observed in this series was similar to
those reported in the literature, despite different
etiologies (infectious vs drug) and various states of
progression in the three cases. In four studies on CsA
treatment for SJS/TEN, the observed time between
initiation of CsA and response was consistently
reported as the dramatic halt of progression observed
after 1.5 to 3 days, regardless of the delay from
disease onset to hospital admission (Table 2) (3,4,7,8).
Many case reports describe even shorter response
times—from hours to 1 to 2 days (5,9–12).
CsA use is associated with faster reepithelialization
rates compared with supportive care of IVIg, which is
 St. John et al: Successful Use of CSA for SJS/TEN 543

further recommendation for its use for the treatment

of stay, days
of SJS/TEN. The patients in this case series experi-

Hospital
length
enced similarly rapid reepithelialization rates (average

11.7
19
12
4
12 days, range 10–15 days), which is similar to those
observed in other case reports (4,7,8,10,13). Treat-
cyclosporine A
Treated with ment with CsA appears to have less effect on wound
healing than treatment with systemic steroids (7), and
some have asserted that CsA’s mechanism of action

14.3
15 promotes reepithelialization (1,13,14).
21
7

CsA has demonstrated significant treatment and

Time to remission or

mortality benefits in adults with SJS/TEN, yet its

reepithelialization,

benefits in children have been described in only two

case reports before this series (13,15). Both cases
describe girls 8 to 10 years of age with TEN who were
concomitantly treated with IV corticosteroids. One
days

13.0
10
15
14

girl experienced an abrupt halt to the rapid progres-

sion of skin lesions within the first 24 hours of CsA
response,
Time to

administration (13) and dramatic improvement was

days

noted in the lesions of the other girl (with 100% BSA

1.5
2.2
2
3

involvement) within 1 to 2 weeks (15). Both girls

treatment, days

survived and returned to their previous states of

diagnosis to

health after resolution of TEN.

Time from

Despite the demonstrated benefits of CsA, much of

the current treatment debate for SJS/TEN centers on
1.0

IVIg versus systemic corticosteroids. Although sam-

2
1
0

ple size and treatment protocols limit many studies,

Delay from disease
onset to hospital

CsA compares favorably with other treatment options

admission, days

BSA, body surface area; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis.

for SJS/TEN. For instance, one study comparing CsA

use with that of cyclophosphamide and steroids for 17
individuals with TEN showed that CsA was associ-
3.3

ated with faster reepithelialization rates, low mortal-

8
0
2

ity, and no significant toxicity despite disease severity

SJS, TEN, overlap

(7). Similarly, another study of 29 patients treated

prospectively with CsA for SJS/TEN found that they
Overlap (25)

experienced a dramatic cessation of progression and

(% BSA)

SJS (15)
SJS (10)
TABLE 1. Patient Characteristics and Clinical Course

lower-than-expected mortality based on results in a

historic cohort treated with IVIg (4). Finally, a more
recent study of 64 patients comparing CsA treatment
Female

with IVIg found a significant trend in mortality

Male
Male
Sex

benefit with CsA (3). Thus a growing body of

literature supports the greater efficacy of CsA than
17 mos

other treatment options.

5 yrs
8 yrs
Age

Despite some variability, there is relative consis-

tency in the literature on CsA dosing, with most
3, then reduced to 1

patients treated successfully with enteral CsA 3 mg/

dose, mg/kg/day

kg/day divided into two doses (3–5,7,8) and a dura-

Cyclosporin A

tion of treatment of 7 to 30 days (Table 2) (3–5,7–

12,16,17). The most desirable dose of CsA is the
lowest dose that is efficacious and not associated with
disease recurrence.
3
3

In this case series, patients were treated with CsA

Average
Patient

3 mg/kg/day divided into two doses for 7, 15, and

21 days, respectively. It is likely that the longer course
1
2
3
TABLE 2. Summary of Previous Literature Reporting the Use of CsA for SJS/TEN
Previous or Time from Time to
concurrent diagnosis remission
treatment Delay to or admission or
with CsA Sex, admission to CsA Time to reepithelia- Hospital
systemic dose, Patients, male/ SJS/overlap/ from onset, treatment, response, lization, Days treated length of Survival to Offending
Author steroids mg/kg/day n Age, years female, n TEN, % days days days days with CsA stay, days discharge Agent

Studies and
case series
Arevalo 3 11 42 (28–82) 3/8 0/100/0 7.4  3.9 1.4  0.3 12.0  3.6 NR 27  25 100%
et al, 2000 (7)
Valeyrie- 3 29 34.2 (17–62) 12/17 35/24/41 2.8  1.8 3 for 65% 12.4  7.7 10; 1-month 16.2  9.1 100%
Allanore taper
et al, 2010 (4)
Firoz et al, Not 8 NR NR 0/0/100 NR NR NR NR NR NR NR
2012 reported
Singh et al, 3 11 32.1  16.2 6/5 45/27.5/27.5 2.6  0.7 NR 3.18  1.32 14.54  4.08 7 (SJS); 18.09  5.02 100%
2013 (8) 14 (TEN)
Kirchhof Yes 3–5 17 53.2  22.2 7/10 64.7/23.5/11.8 8.2  13.2 NR NR NR Average of 7 16.8  8.2 94%
et al, 2014 (3)
Case reports Condition
(% BSA)
Renfro et al, Yes 4 1 35 Female TEN 2 3 2 5 to 6 8 10 Yes Phenytoin
1989 (9)
Hewitt and Yes 3.6 1 34 Female TEN (35) 0 2.5 1.5 NR 10 NR Yes URI
Ormerod, 1992 (5)
Hewitt and Yes 3 1 37 Female TEN (40) 3 1 1 NR 9 NR Yes Amoxicillin
Ormerod, 1992 (5)
Zaki et al, 1995 (11) Yes 4 1 34 Female TEN (>65) 1 ≥2 2 NR 25 NR Yes Amoxicillin
Sullivan and Yes 4.5 1 29 Female TEN (50) 3 7 1 14 16 72 Yes Lamotrigine
Watson 1996 (10)
Szepietowski Yes 10 1 60 Male TEN (60) 0 3 1.5 12-14 10 NR Yes Procaine
et al, 1997 (15) penicillin G
Szepietowski Yes 10 1 48 Male TEN (70) 2 0 2 17 10 NR Yes Acetaminophen
544 Pediatric Dermatology Vol. 34 No. 5 September/October 2017

et al, 1997 (15)

Jarrett et al, Yes 4 1 42 Female TEN (80) 2 0.5 1 15 15 NR Yes Carbamazepine
1997 (12)
Jarrett et al, No 5 1 49 Male TEN (60) 2 0 0 12 12 NR Yes Carbamazepine
1997 (12)
Robak et al, Yes 500 mg/day 1 23 Male TEN (50) 2 0 NR 3 NR 40 Yes Aminopenicillin,
2001 aminophenazone,
acetaminophen
Yung et al, 2002 (17) No 4 1 27 Female TEN (40) 14 3 1 NR NR 17 Yes Dexamphetamine
and ephedrine
Rai and Yes 2 1 40 Male TEN NR 4 NR NR 14 NR Yes Phenytoin
Srinivas, 2008 (16)
Rai and Yes 2 1 55 Female TEN NR 3 NR NR 14 NR Yes Carbamazepine
Srinivas, 2008 (16)
Rai and Yes 2 1 22 Female TEN NR 3 NR NR 14 NR Yes Ciprofloxacin
Srinivas, 2008 (16)
Reese et al, 2011 No 5 1 31 Female TEN (30) 1 0 1 NR NR NR Yes Trimethoprim/
sulfamethoxazole
Reese et al, 2011 No 5 1 21 Female Overlap (17) 1 0 1 NR NR NR Yes Lamotrigine
(discharged
with 30-day
CsA taper)
Reese et al, 2011 No 5 1 28 Female Overlap (15) 3 0 0.5 2 NR NR Yes Trimethoprim/
(discharged sulfamethoxazole
with 30-day
CsA taper)
Reese et al, 2011 No 5 1 31 Male TEN (80) 2 0 0.5 4 NR NR Yes Acetaminophen
Pediatric case
reports
Aihara et al, 2007 (13) Yes 1 (IV) 1 10 Female NR 3 0 3 14 14 38 Yes Acetaminophen
 St. John et al: Successful Use of CSA for SJS/TEN 545

*The authors attribute the patient’s drug reaction to acetylsalicylic acid, but the medication had been started only 4 days before the erythema and bullae formation, whereas carbamazepine
had been started 2 wks before the eruption, which is much more characteristic of an adverse drug reaction; in addition, Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is
for patient 3 was necessary because of disease rebound

Carbamazepine*
upon premature discontinuation of the medication.

Offending
Treatment course may depend on the extent of BSA

Agent
affected, age of the patient, and other comorbidities;
further evaluation on this topic is needed, although
Survival to
discharge much of the research indicates that low-dose CsA of 3
to 4 mg/kg/day is sufficient for adequate treatment of
Yes
SJS/TEN (4,5,7–9,11,12,16,17). We therefore propose
1 week of CsA 3 mg/kg/day followed by 1 week of
stay, days
length of
Hospital

CsA 1.5 mg/kg/day (both divided into two doses) as a

NR

complete course of therapy for SJS/TEN. Manage-

ment of long-term sequelae includes ocular care and
Days treated

outpatient support.
with CsA

Low-dose CsA use in children for chronic idiopathic

21

urticaria has been documented for up to 6 months

without adverse effects (18,19). Adverse effects com-
reepithelia-
remission

monly associated with CsA use, such as hypertension

lization,
Time to

days

and immunosuppression, are often associated with

14
or

higher treatment doses (5–15 mg/kg/day) and longer

a known serious adverse reaction to carbamazepine, whereas acetylsalicylic acid has not been associated with SJS/TEN.

courses of therapy (7,20). Nephrotoxicity is associated

response,
Time to

with treatment doses greater than 5 mg/kg/day and

days

longer treatment courses (7,20). In patients with

or admission

adequate renal function, daily monitoring of CBC

Time from

treatment,
diagnosis

with differential and a comprehensive metabolic

to CsA

days

panel is adequate for making dose adjustments as

0

necessary in patients treated with CsA (4,13).

from onset,
admission
Delay to

Literature on the treatment of SJS/TEN in children

days

is remarkably sparse (1) and what research exists

0

focuses on the treatment debate between corticos-

SJS/overlap/

teroids and IVIg (1,2). This case series provides

TEN (100)
TEN, %

additional evidence that CsA is an efficacious treat-

ment and suggests it may be used as a monotherapy in
children with SJS/TEN. Additional trials are needed
female, n

Female
male/

to evaluate the safety and efficacy of CsA use in

Sex,

children. Nevertheless, CsA is associated with sub-

stantial clinical improvement in halting disease pro-
Age, years

gression and fostering reepithelialization in patients

with SJS/TEN and has a demonstrated safety profile.
8

These results are promising and deserve further

Patients,

investigation.
1
n
mg/kg/day

CsA, cyclosporine A; NR, not reported.

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