DERMATOLOGICA SINICA 35 (2017) 131e137

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ORIGINAL ARTICLE

Efficacy of cyclosporine for the treatment of Stevens-Johnson

syndrome and toxic epidermal necrolysis: Systemic review and
meta-analysis
Yu-Tsung Chen a, b, d, Che-Yuan Hsu a, d, Yu-Ning Chien b, Woan-Ruoh Lee a, d,
Yu-Chen Huang c, d, *
a
Department of Dermatology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
b
School of Public Health, College of Public Health and Nutrition; Taipei Medical University, Taipei, Taiwan
c
Departments of Dermatology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
d
Departments of Dermatology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening
Received: Oct 7, 2016 reactions, mainly to drug, characterized by epidermal necrosis and mucous membrane ulceration.
Revised: Apr 2, 2017 SCORTEN-predicted mortality has been used to assess the efficacy of treatments comparing with actual
Accepted: Apr 12, 2017
mortality. Several literatures about cyclosporine have shown its ability to halt disease progression and
decrease mortality.
Keywords:
Objectives: This study was aimed to provide a more evidence-based review by conducting a meta-
Cyclosporine
analysis of cyclosporine for the treatment of SJS/TEN.
Meta-analysis
Stevens-Johnson syndrome
Methods: We conducted a systemic review of articles published before Jan 31, 2017. The outcomes were
Systemic review mortality rate and SCORTEN-based standardized mortality ratio (SMR). The pooled odds ratio (OR) and
Toxic epidermal necrolysis SMR ratio were analyzed from these extracted data.
Results: There were 7 observational controlled studies (1 historical controlled study) which met the
inclusion criteria. The overall mortality rate for patients receiving cyclosporine was 7.1%. The observed
mortality was significantly lower than predicted mortality in patients receiving cyclosporine (pooled
SMR: 0.42; 95% CI, 0.19e0.95). The pooled estimate of ORs for 4 studies describing observed mortality in
cyclosporine to intravenous immunoglobulins (IVIg) group was 0.40 (95%CI, 0.06e2.69). Comparison of
SMR between cyclosporine and IVIg was presented with the pooled SMR ratio, which showed no sig-
nificant difference in SMR ratio between two treatments (SMR ratio, 0.49, 95% CI, 0.08e2.89).
Conclusion: We have provided the first meta-analysis study regarding the efficacy on mortality of
cyclosporine for treatment of SJS/TEN. From the existing research, cyclosporine has a beneficial effect on
mortality. And there is a trend that cyclosporine demonstrated better survival whether in pooled OR or
SMR ratio than IVIg. Due to the limitations of current studies, a double-blind randomized controlled trial
is still urged.
Copyright © 2017, Taiwanese Dermatological Association.
Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction These conditions are characterized by epidermal necrosis and mu-

StevenseJohnson syndrome (SJS) and toxic epidermal necrolysis
(TEN) are life-threatening conditions that arise as reactions to drugs.
Conflicts of interest: The authors declare that they have no financial or non-
financial conflicts of interest related to the subject matter or materials discussed
in this article.
* Corresponding author. Department of Dermatology, Wan Fang Hospital, Taipei
Medical University, No. 111, Section 3, Hsing-Long Rd, Taipei 116, Taiwan. Fax: þ886
5 3623002.
E-mail address: dhist2002@yahoo.com.tw (Y.-C. Huang).
cous membrane ulceration,1 and their presentations are differenti-
ated by the extent of body surface area (BSA) affected. Patients with
less than 10% BSA involved are classified as having SJS, 10%e30% BSA
as SJS/TEN overlap, and >30% BSA as TEN.2 Although the incidence of
these conditions is very low, the associated mortality rates are quite
high, ranging from 1% to 5% in SJS and 25%e30% in TEN.3 A prognostic
scoring system, severity-of-illness score for TEN(SCORTEN), was
developed and validated to predict mortality in patients with SJS or
TEN,4,5 and SCORTEN-based mortality rates have been used to assess
the efficacy of treatments for these conditions.6,7

http://dx.doi.org/10.1016/j.dsi.2017.04.004
1027-8117/Copyright © 2017, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
132 Y.-T. Chen et al. / Dermatologica Sinica 35 (2017) 131e137
Treatment for SJS and TEN is identification and withdrawal of
the offending agent with supportive care. Systemic treatments,
including systemic steroids, intravenous immunoglobulin (IVIg),
and cyclosporine, have been studied for SJS and TEN. Due to an
increased risk of complications associated with corticosteroid
use,8,9 treatment with IVIg or cyclosporine has increased among
clinicians. Studies on the effect of IVIg on mortality rates have re-
ported conflicting results10,11; however, several case reports and
series on cyclosporine have reported its ability to halt disease
progression and reduce mortality rates.12e14 In this study, we
conducted a meta-analysis and an evidence-based review on the
effects of cyclosporine treatment on SJS/TEN.
Methods
Review protocol
Recommendations of the Preferred Reporting Items for Systematic
Reviews and Meta-analyses (PRISMA) statement, explanation and
elaboration document, and checklists were followed as closely as
possible to guide our methodology and reporting.15
Eligibility
We primarily focused our literature search on randomized
controlled trials (RCTs); however, in the absence of randomized
controlled trials, we included observational controlled studies that
Fig. 1 The flow chart showed how the studies were selected. Seventy-six were initially identified through the initial search strategy. Consequently, 6 studies were included in this review.
evaluated patients with 3 SJS, SJS/TEN overlap, or TEN receiving
cyclosporine monotherapy. A controlled study was defined as a
study that evaluated patients with 3 SJS, SJS/TEN overlap, or TEN
receiving another kind of therapy within the same study. Review
articles, letters, case reports, and conference reports were excluded.
Articles that were not written in English were excluded.”
Search strategy
We searched PubMed, MEDLINE, EmBase, and the Cochrane Library
(including The Cochrane Database of Systematic Reviews, the
Database of Abstracts of Reviews of Effects, The Cochrane
Controlled Trials Register, and The Health Technology Assessment
Databases) from their inception to Jan 31, 2017. All studies used for
our analysis consisted of human clinical studies. The MeSH search
headings included (“Stevens-Johnson syndrome “OR “toxic
epidermis necrolysis”) AND (“Cyclosporine” OR “Cyclosporin”).
References within searched articles were also reviewed to identify
potentially missed studies.
Study selection
The titles and abstracts of articles were first screened for eligibility
by Y.T. Chen. The full texts of selected articles were independently
reviewed by Y.T. Chen and Y.C. Huang. Articles irrelevant to our
topic, based on title, abstract, and overall content were excluded.
We also excluded articles without a full-text version of the
Table 1 Summary of the trial characteristics from each of the seven studies.

Study (year) Study design Country Inclusion dates Sample size and Treatment group SCORTEN(n) Treatment dose Author's conclusion
classification

Cyclosporine vs IVIg
Rajaratnam et al. (2010) Retrospective United 1995-2007 TEN: 21 IVIg: 14 score 0: 0 IVIG: 0.4-1.0 g/kg/day Benefit from IVIg
Kingdom Cyclophosphamide: 2 score 1: 0 for 3-7 days
Cyclosporine: 3 score 2: 6 Cyclophosphamide:
score 3: 7 2.5 mg/kg/day for 3
score 4: 4 days.
score 5: 2 Cyclosporine: 2.5-4 mg/
kg/day for 3-5 days.
Valeyrie-Allanore et al. 2010 Retrospective France 2005-2007 SJS: 12 Cyclosporine: 29 Mean: 1.27 Cyclosporine: 1.5 mg/ Cyclosporine is more effective
historical SJS/TEN: 10 kg twice daily, 1 mg/kg
controlled TEN: 7 twice daily and 0.5 mg/
kg twice daily for 10
days, respectively.
N/A IVIg: 34* Mean: 2.17 N/A
Firoz et al (2012) Prospective America N/A TEN: 82 IVIg: 23 score 0: 5 IVIg: 4 g/kg divided No significant difference in
Cyclosporine: 8 score 1: 14 over 3 days. survival between supportive
Supportive care: 51 score 2: 25 Cyclosporine: not care, IVIg, and cyclosporine.

Y.-T. Chen et al. / Dermatologica Sinica 35 (2017) 131e137

score 3: 20 mentioned.
score 4: 17
score 5: 1
Kirchhof et al (2014) Retrospective Canada 2001-2011 SJS: 28 IVIG: 37 score 0: 2 IVIg: 1 g/kg/d for 3 days. Cyclosporine is better
SJS/TEN: 19 score 1: 12
TEN: 17 score 2: 11
score 3: 6
score 4: 5
score 5: 1
Cyclosporine: 17 score 0: 3 Cyclosporine: 3-5 mg/
score 1: 6 kg/d orally or
score 2: 3 intravenously for an
score 3: 4 average of 7 days.
score 4: 1
score 5: 0
Cyclosporine vs other therapy
valo et al. (2000)
Are Retrospective Spain 1995-1999 TEN: 17 Cyclosporine: 11 N/A 3 mg/kg per day for 2 Cyclosporine is more effective
weeks than treatment with
Cyclophosphamide þ N/A Cyclophosphamide: cyclophosphamide and
corticosteroids: 6 150 mg i.v. every 12 corticosteroids.
hours.
Corticosteroid:
different doses and
days.
Singh et al. (2013) Retrospective India 2011-2012 SJS: 8 Cyclosporine: 11 score 0: 2 Cyclosporine: 3 mg/kg Cyclosporine is more effective
SJS/TEN: 4 score 1: 3 in three divided than corticosteroid.
TEN: 5 score 2: 5 dosages for 7 days, then
score 3: 1 2 mg/kg in two divided
score 4: 0 dosage for another 7
score 5: 0 days.
Corticosteroid: 6 score 0: 2 Steroid:
score 1: 3 dexamethasone
score 2: 0 followed by oral
score 3: 1 prednisolone in the
score 4: dosage of 1 mg/kg/
0 score 5: 0 day.
(continued on next page)

133
 134 Y.-T. Chen et al. / Dermatologica Sinica 35 (2017) 131e137

manuscript available. Review articles, letters, and case reports were

also excluded. If overlapping data sets were described in different
Cyclosporine is more effective

publications, the study with the larger population was included.

Disagreement between the reviewers was resolved by consensus.
than supportive care.
Author's conclusion

Data extraction

Y.T. Chen independently extracted and synthesized data in a tabular

format, and these tables were double-checked for accuracy by Y. C.
Huang. The definition of SJS, SJS-TEN overlap, and TEN was based on
the original study. The extracted data were as follows: study design,
sample size, country, inclusion dates, treatment regimen, age,
Cyclosporine: 3 mg/kg/
d for 10 days, followed

days, and lastly 1 mg/

gender, TBSA, observed death, predicted death, mortality rate, and

by 2 mg/kg/d for 10

Corticosteroid: N/A

SCORTEN-based standardized mortality ratios (SMR) with 95% CI.

kg/d for 10 days.
Treatment dose

Patients were divided into groups based on treatment as follows:

IVIg: 1 g/kg/d

cyclosporine and other systemic steroids, cyclophosphamide, and

IVIg groups. If data on mortality was not reported in an original
publication, corresponding authors were contacted to obtain raw
data.
SCORTEN(n)

Outcomes
0-1: 5

0-1: 1

0-1: 7
2: 3
3: 9
4: 1
5: 1

2: 1
3: 1
4: 1
5: 1

2: 2
3: 7
4: 2
5: 2
score
score
score
score
score
score
score
score
score
score
score
score
score
score
score

The outcomes evaluated included mortality rates and SMRs. The

SCORTEN system was initially developed and validated by Bastuji-
Garin et al.4 and is scored as follows: a SCORTEN score of 0e1
predicts a mortality rate of 3.2%; a score of 2 predicts a mortality
IVIg/corticosteroids: 5

Supportive care: 20

rate of 12.1%, a score of 3 predicts a mortality rate of 35.3%, a score

Treatment group

Cyclosporine: 19

of 4 predicts a mortality rate of 58.3%, and a score of 5 predicts a

Cyclosporine þ

mortality rate of 90.0%. For each study, expected mortality rates

were calculated from the reported SCORTEN scores by multiplying
the number of cases with each SCORTEN score by the predicted
mortality rate; the observed mortality rate was calculated based on
the number of actual deaths reported for each SCORTEN score. SMR
was defined as observed deaths/expected deaths.
Sample size and
classification

SJS/TEN: 12

Data analysis
TEN: 16
SJS: 16

For all included studies, we calculated the pooled crude mortality

rate of patients receiving cyclosporine and produced a pooled es-
timate of risk for mortality of patients treated with cyclosporine
Inclusion dates

compared to patients receiving an alternate therapy when there

2011-2014

was more than one study on the therapy. The results were
expressed as overall odds ratios (ORs) with associated 95% CI. For all
studies providing SCORTEN scores of patients, SMR was calculated
as above, and the accompanying 95% CI was based on the method of
Ury and Wiggins.16 We produced a pooled SMR for cyclosporine
Singapore

treatment and other therapies (when there was more than one
Country

study), with the results expressed as overall SMR and associated

95% CI. A pooled estimate ratio of SMR of patients treating with
cyclosporine compared to patients receiving alternate therapies
was also performed. Homogeneity testing was performed using the
Retrospective
Study design

I2 test. A random effects model was used for all analyses due to the
large heterogeneity of the sample. When the mortality rate was 0,
we added 0.5 to each cell for calculations. Analysis was performed
using MetaXL version 5.2.

Results

Fig. 1 shows a flow chart describing how the studies were selected.
Table 1 (continued )

Of the 172 studies screened by title and abstract, 146 were excluded
Lee et al. (2017)

because they were non-relevant; 19 non-controlled studies were

Study (year)

further excluded. Therefore, seven studies were included in this

review. A summary of the trial characteristics from each of the
seven studies are shown in Table 1. The studies were published
between 1995 and 2017 and included sample sizes ranging from 17
 Y.-T. Chen et al. / Dermatologica Sinica 35 (2017) 131e137 135

to 82. The seven controlled studies compared the mortality rates in
patients treated with cyclosporine vs. IVIg (4 studies), corticoste-
roid (1 study), cyclophosphamide and steroids (1 study), or sup-
portive care (2 studies, 1 study overlapped with IVIg). A total of 98
patients (35 SJS, 24 SJS/TEN overlap, and 39 TEN patients) received
cyclosporine treatment. Cyclosporine was reported to have a
significantly higher benefit than IVIg,2 corticosteroid,14 and com-
bined cyclophosphamide and corticosteroid treatment.12 One
historical-controlled study showed a benefit in mortality rate and
progression of detachment in comparison to a historical group
receiving IVIg.6 Two other studies suggested a benefit from IVIg
treatment17 and did not find a significant difference in survival rate
between IVIg, cyclosporine, and supportive care.18
Table 2 provides detailed information on age, gender, average
BSA, mean hospital stay, mortality (observed and predicted), and
SMR. The mean age of patients receiving cyclosporine and IVIg
were 43.93 ± 8.40 years and 50.11 ± 4.17 years, respectively, and
there was significant difference in age between the two groups
(p < 0.001). The mean BSA of patients receiving cyclosporine and
IVIg were 28.96 ± 21.94 and 28.93 ± 8.27, respectively, but there
was no significant difference between the two groups. The overall
mortality rate was 7.1% (7/98) Approximately, patients receiving
cyclosporine had a lower mean hospital stay (17.30 days) compared
to those receiving IVIg (23.19 days) or steroids (26 days).
In this meta-analysis, the observed mortality was significantly
lower than predicted mortality in patients receiving cyclosporine
(SMR: 0.42; 95% CI, 0.19e0.95; I2 ¼ 0%) (Fig. 2a). Patients in the
cyclosporine group had lower SMR values than the IVIg group in
two studies (0 vs. 1.375; 0.42 vs.1.43); conversely, another study
showed lower SMR values in the IVIg group (0.567 vs. 1.54)
compared to the cyclosporine group. The pooled estimate of ORs for
four studies describing the observed mortality rate in the cyclo-
sporine group to the IVIg group was 0.4 (95% CI, 0.06e2.69;
I2 ¼ 62%) (Fig. 2b). Among these studies, only three studies
describing the predicted mortality were analyzed for pooled SMR
ratio. And pooled SMR ratios between the cyclosporine and IVIg
groups were not significantly different (0.49, 95% CI, 0.08e2.89;
I2 ¼ 22%) (Fig. 2c).
Discussion
Keratinocyte apoptosis causes epidermal necrosis in SJS/TEN.19
Cytotoxic T-cells and FaseFas ligands, which are also thought to
play a crucial role, are blocked by cyclosporine and IVIG, respec-
tively.20 In our meta-analysis, the overall mortality rate was 7.1%,
and the pooled SMR was 0.42 for the cyclosporine group, indicating
a beneficial effect on mortality. Although there were no significant
differences in the pooled ORs and SMR ratios between the cyclo-
sporine and IVIG groups, there was a trend toward lower mortality
rates in the cyclosporine group.
Mixed results have been reported in the literature regarding
IVIG as several studies have shown that IVIG does not provide a
mortality benefit.11,21,22 These results may be attributed to
different dosing (low dose versus high dose), timing of initiation,
or comorbidities of the different patient populations evaluated.
Several studies have reported a mortality benefit from cyclo-
sporine due to its immunosuppressive inhibition of CD8þ cyto-
toxicity.6,12,14,23 Based on our review and meta-analysis, both SMR
and mean hospital stay in cyclosporine group were lower than in
the IVIG group; however, due to its toxicity, the inclusion criteria
set for those in the cyclosporine group were strict to avoid
immunosuppression and renal impairment.24 These criteria
resulted in a population of younger patients in good health6,14 by
excluding patients with severe comorbidities, including renal
insufficiency, multi-organ failure, sepsis, and HIV, which could
lead to a higher mortality rate; thus, our selection of patients may
have confounded the comparison between the cyclosporine and
IVIg groups.
In our literature review, we found that various culprit drugs
have been reported to induce SJS/TEN, and the diversity of these
drugs could bias mortality rate analysis. Firoz et al.18 reported that
allopurinol was associated with the mortality in contrast to other
drugs. This finding could be attributed to the longer half-life of
oxypurinol, an active metabolite of allopurinol, which remains in
the bloodstream for longer and induces a cascade resulting in SJS/
TEN.25 A more detailed analysis of mortality rates for individual
drugs could help clarify the SMR, which has yet to be done.

Table 2 Detailed information on age, gender, average BSA, mean hospital stay, mortality (observed and predicted), and standardized mortality ratio.

Study (year) Age(y) Male(%) Average Mean Hospital Observed Predicted Standardized Confidence
BSA(%) stay(day) mortality mortality mortality ratio interval

Cyclosporine vs IVIg

Rajaratnam et al. (2010)

Cyclosporine 54(18-86) 38.10% 44% 20.4 2 1.287 1.54 0.18-5.34
IVIG 3 5.021 0.59749054 0.12-1.69
Valeyrie-Allanore et al. (2010)
Cyclosporine 34.2 ± 14.1 N/A 12.20% 16.2 0 2.75 0 0.36-0.76
IVIG 47 ± 21 N/A 19 N/A 11 8 1.375 0.69-3.45
Firoz et al (2012)
Cyclosporine 45.1 ± 20.4 53.65% 34.80% 17 2 N/A N/A N/A
IVIG 7 N/A N/A N/A
Supportive care 15 N/A N/A N/A
Kirchhof et al (2014)
Cyclosporine 53.2 ± 22.2 41.20% 16.30% 16.8 1 2.4 0.42 0.017-2.11
IVIG 54.6 ± 20.6 48.60% 28.70% 26.6 11 7.7 1.43 0.71-2.55

Cyclosporine vs other therapy

valo et al. (2000)
Are
Cyclosporine 42.18 ± 20.2 27.30% 83% 27 0 N/A N/A N/A
Cyclophosphamide þ Corticosteroid 56.66 ± 8.8 67% 77.5% 19.67 3 N/A N/A N/A
Singh et al. (2013)
Cyclosporine 32.09 ± 16.2 54.54% 23.36% 18.09 0 1.11 0 0.89-1.87
Steroid 27.87 ± 13.9 50% 22.17% 26 2 0.51 3.92 0.66-12.96
Lee et al. (2017)
Cyclosporine 51.15 63% 24.2% 13 2 5.3 0.38 0.04-1.30
Supportive care 66 ± 17 65% 32% 14 6 5.9 1.02 0.37-2.21
136 Y.-T. Chen et al. / Dermatologica Sinica 35 (2017) 131e137

Fig. 2 (a) The pooled SMR for patients receiving cyclosporine was 0.43 (95% CI, 0.19e0.95). (b) The pooled estimate of ORs for 4 studies describing observed mortality in cyclo-
sporine to IVIg group was 0.40 (95%CI, 0.06e2.69). (c) Comparison of SMR between cyclosporine and IVIg with the pooled SMRratio, which showed no significant difference (SMR
ratio, 0.49, 95% CI, 0.08e2.89). OR, odds ratio; SMR, standardized mortality ratios.

Additional factors, such as age 40 years, higher SCORTEN
scores, and higher BSA percentages, can lead to poorer survival.18 In
our review, both groups had a mean age of 40 years but the mean
age was significantly higher in the IVIg group, which could explain
higher mortality rates. However, only crude data was analyzed by
univariate analysis since, and some of the patients had received
corticosteroids before admission to the intensive care unit. In
Arevalo's study,12 most patients who received cyclosporine were
treated with corticosteroids before admission; however, they
showed better outcomes. Other factors, including early recognition
and treatment for infection, wound management, or aggressive
surgical treatment, could have affected the outcome in our study as
well. All these factors should be considered when comparing these
conflicting results. To clarify these differences, randomized
controlled trials should be conducted.
There were some limitations of our study. The severity of the
conditions of patients varied in this study. Therefore, there were
patients with mild SJS whose condition may not have worsened if
untreated, while there were patients with severe TEN who would
probably not have survived even after aggressive treatment. To
account for these differences, we used SMR by SCORTEN scores at
admission to achieve standardization across different disease
states. Another limitation is the heterogeneity in dosing and timing
of cyclosporine and IVIG treatments, which increased bias; how-
ever, a double-blind randomized controlled trial was not feasible
due to the rarity of disease as to recruit sufficient patients. There-
fore, we use a meta-analysis to minimize the effect of a relatively
small sample size and heterogeneity in treatment.
In summary, we provide the first meta-analysis on the efficacy
of cyclosporine on mortality in patients with SJS/TEN. Patients
 Y.-T. Chen et al. / Dermatologica Sinica 35 (2017) 131e137
treated with cyclosporine showed a lower mortality rate and SMR.
Based on existing data, we found that cyclosporine treatment
tended to improve survival whether in pooled OR or SMR ratio
compared to IVIg. Due to the limitations of current study, a double-
blind randomized control study would provide greater clarity.
Acknowledgments
We thank Dr. Haur Yueh Lee of the Department of Dermatology and
Allergy Center, Singapore General Hospital, Singapore for gener-
ously providing the detailed data of the study titled ‘Cyclosporine
treatment for Stevens-Johnson syndrome/toxic epidermal necrol-
ysis: Retrospective analysis of a cohort treated in a specialized
referral center’.
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