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Available online at www.sciencedirect.com

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Combination therapy: Etanercept and intravenous

immunoglobulin for the acute treatment of Stevens-
Johnson syndrome/toxic epidermal necrolysis

Christopher H. Pham a,b, T. Justin Gillenwater a,b, Eric Nagengast b,

Meghan C. McCullough b , David H. Peng a,c , Warren L. Garner a,b, *
a
Keck School of Medicine, University of Southern California, 1975 Zonal Avenue, Los Angeles, CA 90033, United States
b
Division of Plastic Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, 1510
San Pablo Street, Suite 415, Los Angeles, CA 90033, United States
c
Department of Dermatology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue,
Ezralow Tower, Suite 5301, Los Angeles, CA 90033, United States

article info abstract

Article history: Background: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is an autoim-

Accepted 22 December 2018 mune condition with significant morbidity and mortality.
Available online xxx Methods: A retrospective review was performed at a single institution. All patients admitted
to the LAC+USC burn unit from May 1st 2015–January 1st 2018 with a histologic diagnosis of
SJS/TEN were reviewed. Patient characteristics and outcomes were recorded. These
Keywords:
outcomes were compared to our previously published cohort.
Burns
Results: Thirteen total consecutive SJS/TEN patients were treated with etanercept. Compared
Dermatology
to non-etanercept treated patients, etanercept-treated patients did not experience a
Plastic surgery
significant difference in mortality (15.4% vs. 10%, P=0.58), ICU days (6.9 vs. 15.1, P=0.08),
Toxic epidermal necrolysis
length-of-stay (9.8 vs 16.4, P=0.11), or infections (38.5% vs. 57.5%, P=0.58). The standardized
Stevens-Johnson syndrome
mortality ratio in etanercept-treated patients was 0.44 (95% CI, 0.21, 0.65). In general,
etanercept-treated patients had higher SCORTENs (3 vs. 2, P=0.03) and longer delays to
presentation (5.2 vs. 2.7 days, P<0.01).
Conclusions: Etanercept can be considered in the treatment of SJS/TEN patients in addition to
IVIg, and supportive care in a burn unit.
© 2019 Elsevier Ltd and ISBI. All rights reserved.

autoimmune disease that is poorly characterized. The

1. Introduction
etiology of this disease is not well understood but is
thought to be a response to exogenous stimuli, most
Stevens-Johnson syndrome (SJS)/toxic epidermal commonly secondary to drug reactions and microbial
necrolysis (TEN) is a life-threatening cutaneous infections [1].

Abbreviations: SJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysis; SMR, Standardized mortality ratio; TNF, Tumor necrosis
factor; IVIg, Intravenous immunoglobulin.
* Corresponding author at: Plastic and Reconstructive Surgery, Burn and Critical Care, Univ. of Southern California, LAC+USC Burn Center,
2051 Marengo St., Los Angeles, CA 90033, United States.
E-mail address: wgarner@med.usc.edu (W.L. Garner).
https://doi.org/10.1016/j.burns.2018.12.018
0305-4179/© 2019 Elsevier Ltd and ISBI. All rights reserved.

Please cite this article in press as: C.H. Pham, et al., Combination therapy: Etanercept and intravenous immunoglobulin for the acute
treatment of Stevens-Johnson syndrome/toxic epidermal necrolysis, Burns (2019), https://doi.org/10.1016/j.burns.2018.12.018
JBUR 5741 No. of Pages 5
2 burns xxx (2019) xxx –xxx
Most practitioners use the previously validated “severity-
of-illness score” (SCORTEN) [2] for estimating the mortality of
SJS/TEN and to compare outcomes between different treat-
ment modalities. During the last several years there has been
controversy regarding the best treatment for these patients
and our institution recently published our 15-year experience
with this disease and documented a mortality rate of 10% [3].
Our treatment algorithm [3] includes a multi-disciplinary team
of burn surgeons, dermatologists, ophthalmologists, critical
care nurses, and registered dietitians. We employ aggressive
fluid resuscitation (titrated to a urine output of 0.5–1.0 cc/kg/
hr), mechanical debridement to remove sloughed epidermis
and exudate, wound care with a nondaily silver dressing
(Exsalt, Exciton Technologies), and enteral nutrition to
optimize wound healing.
Corticosteroids, intravenous immunoglobulin (IVIg), cyclo-
sporine, and supportive care have all been documented as
treatment modalities for SJS/TEN, with controversy surround-
ing all modalities except supportive care. Corticosteroid use
has been shown to provide ocular benefits in SJS/TEN [4], but
some have argued there is an association with higher mortality
[5,6]. Meta-analysis has also questioned the role of IVIg [7]. In
addition to supportive care, some have successfully reported
treating SJS/TEN with Infliximab [8–15], a TNF-alpha monoclo-
nal antibody that inhibits binding at its receptor, and with
etanercept, a TNF-alpha decoy receptor [16–21] Here, we
present a series of patients treated with etanercept, IVIg,
and supportive care and believe that it may lead to improved
outcomes.
2. Methods
After obtaining Institutional Review Board approval (Protocol
Number: HS-15-00173), we performed a retrospective chart
review from May 1st 2015–January 1st 2018 to examine all
consecutive patients admitted to the LAC+USC burn unit
diagnosed with SJS/TEN, confirmed by histology, and treated
with etanercept. The histologic diagnosis of SJS/TEN was
confirmed when full-thickness epidermal necrosis with a
lymphocytic infiltrate was observed. The culprit drug or
Table 1 – Patient characteristics.
Etanercept-treated
Age (years) 44.8 21.1
Male 5 (38.5%)
Female 8 (61.5%)
Total body surface area (%) 54.3
SCORTEN 3 2.1
Total ICU stay (days) 6.9
Total length-of-stay (days) 9.8
Time-to-burn unit (days) 5.2
Causative agent (%)
Antibiotics 5 (38.5%)
Antiepileptics 3 (23.1%)
Allopurinol 1 (7.7%)
Undetermined 4 (30.8%)
*
Denotes statistical significance (P <0.05).
Please cite this article in press as: C.H. Pham, et al., Combination therapy: Etanercept and intravenous immunoglobulin for the acute
treatment of Stevens-Johnson syndrome/toxic epidermal necrolysis, Burns (2019), https://doi.org/10.1016/j.burns.2018.12.018
infection was determined through a thorough history and
application of the ALDEN method [22]. The culprit drug was
identified when an ALDEN score greater than or equal to 4 [22]
was calculated; otherwise, the culprit drug was listed as
“Undetermined” (Table 1). Patient characteristics (age, sex,
medical co-morbidities), disease characteristics (greatest total
body surface area involvement, time-to-burn unit, causative
agent, SCORTEN), and treatment modalities (steroids, IVIg,
etanercept) were examined. The primary outcome was
mortality and secondary outcomes included rates of hospital
complications, total ICU days, and total hospital days. Hospital
complications included respiratory failure (defined as under-
going intubation), renal failure (receiving hemodialysis (HD) or
continuous renal replacement therapy (CRRT)), shock
(hypotension receiving vasopressor support), infection
(defined as a positive culture), or ocular involvement with
an ophthalmology consult.
The etanercept-treated cohort was compared against our
previously published cohort of patients not treated with
etanercept. All patients — etanercept and non-etanercept —
received IVIg and wound care with silver-impregnated
products, with the only difference in treatment being the
presence or absence of etanercept. Etanercept is routinely
given within the first 24h of admission at our burn center.
All data was analyzed using IBM SPSS Statistics Software
Package. Categorical data (e.g., patient characteristics) were
compared by Fischer’s Exact and chi-squared tests and
considered significant when P<0.05 (95% confidence
interval, CI). Continuous variables were compared by two-
tailed t-tests. Linear and logistic regressions were used to
estimate the effect of etanercept on the outcomes of interest.
The family of tests used to test hypotheses around the effect
of etanercept were considered significant when P<0.005
(Bonferroni Correction, 0.05/10 hypotheses). Per a previously
published method [3,23,24], standardized mortality ratios
(SMR) were calculated using the observed mortalities and
expected mortalities as predicted by SCORTEN. Because of
the lack of a control cohort, SMRs between etanercept and
non-etanercept treated patients cannot be compared with
statistics and, instead, are reported with their respective 95%
confidence intervals.
Non-etanercept P
45.9 20.0 0.9
18 (45%)
22 (55%)
46.3 0.3
0.03*
15.1 0.08
16.4 0.11
2.7 <0.01*
19 (47.5%)
8 (20%)
6 (15%)
7 (17.5%)
JBUR 5741 No. of Pages 5

burns xxx (2019) xxx –xxx 3

statistically significant, we noted that etanercept tended

3. Results
Thirteen patients with a histologic diagnosis of SJS/TEN were
treated with etanercept, IVIg, and supportive care during the
study period and compared to our previously published cohort
[3] of 40 patients only treated with IVIg and supportive care.
There was no significant difference between age, sex, or
cause of SJS/TEN between cohorts (Table 1). In general,
etanercept-treated patients had significantly more severe
presentations characterized by higher SCORTENs (3 vs. 2.1,
P=0.03) and longer delays before presenting to our burn unit
(5.2 vs. 2.7 days, P<0.01). There was a trend toward more skin
involvement (54.3% vs. 46.3%, P=0.30) in etanercept-treated
patients although this did not reach statistical significance
(Table 1).
There was no difference in mortality between etanercept
and non-etanercept treated patients (15.4% vs. 10%, P=0.58)
(Table 2). Using the predicted mortality from individual patient
SCORTENs, the standardized mortality ratio (SMR) for etaner-
cept-treated patients was 0.44 (95% CI, 0.21, 0.65) (Table 2).
Etanercept-treated patients tended toward fewer ICU days
(mean, 6.9 vs. 15.1 days, P=0.08) and a shorter total LOS (mean,
9.8 vs. 16.4 days, P=0.11) although these findings were not
statistically significant (Table 1). Logistic and linear regres-
sions (Table 3) to estimate the effects of etanercept did not
show significant differences in any outcome. Although not
Table 2 – Mortality and standardized mortality ratio.
SCORTEN Etanercept-treated Non-etanercept
(N) (N)a
0–1 0 11
2 5 11
3 4 7 and supportive care alone. Although it did not reach statistical
4 3 3 significance, we also noted that patients treated with
5 1 1 etanercept tended toward fewer ocular complications. We
Unable to – 7
determine
Mortality (%) 2 (15.4) 4 (10)
SMR (95% CI) 0.44b (0.21, 0.65) 0.60b (0.23, 0.97)
a
Adapted from McCullough et al.
b patient in our entire SJS/TEN database developed blindness.
Denotes statistical significance (95% CI).
Table 3 – Multivariate regression of Etanercept on
outcomes: normal linear regression for continuous
variables; logistic regression for dichotomous variables.
Mortality, HD/CRRT, and ocular complications could not be
included in the regression due to a lack of data. No
significant values (P<0.005, Bonferroni correction).
toward reducing total LOS by 12.8 days (P=0.07).
There were no significant differences in infectious com-
plications between etanercept-treated and non-etanercept
treated patients (38.5% vs. 57.5%, P=0.58) (Table 4). There were
also no significant differences in the incidence of respiratory
failure with intubation (15.4% vs. 47.5%, P=0.59), hypotension
receiving vasopressor support (23.1% vs. 17.5%, P=0.50), renal
failure undergoing HD or CRRT (15.4% vs. 5%, P=0.38), or ocular
complications in patients treated with etanercept (15.4% vs.
35%, P=0.10) (Table 4).
4. Discussion
We described and compared the characteristics and outcomes
of patients treated with etanercept in addition to IVIg and
supportive care against a previously published [3] cohort
treated only with IVIg and supportive care for the treatment of
SJS/TEN. The two cohorts were similar in age, sex, and cause of
disease (Table 1).
Although we did not detect a significant difference in
mortality between groups, this must be analyzed in the
context of significantly higher SCORTENs (P=0.03), and longer
delays-to-presentation at the burn unit (P<0.01) in etanercept-
treated patients. The higher SCORTENs and longer delays to
transfer in the etanercept-treated patients may be explained
by stochasticity as a result of our sample size rather than a
demographic change. Among our etanercept-treated patients
(mean SCORTEN 3, expected 35.3% mortality), the SMR was
0.44 and statistically significant (95% CI, 0.21, 0.65). When
comparing the SMRs of our etanercept vs. non-etanercept
cohort, the etanercept-treated cohort had a lower SMR (0.44 vs.
0.60) (Table 2). Thus, it appears that patients treated with
etanercept, IVIg, and supportive care appeared to have some
improvement in mortality compared to those treated with IVIg
currently employ amniotic membrane transplantation (AMT)
on all patients with ocular involvement due to data demon-
strating a significant effect on preventing vision loss in
patients treated with AMT [25]. Detailed visual acuity data
was not available in our study, but we note that only one
Of the two patients (XX and YY) that died in our etanercept-
treated cohort, one (XX) had a SCORTEN of 5 (expected
mortality >90%), 90% TBSA involvement, and died from
Vancomycin-resistant enterococcal sepsis. The other (YY)
Table 4 – Hospital complications. No significant values
(P<0.005, Bonferroni correction).

Outcome Effect estimate (Std. Error) P Etanercept-treated Non-etanercept P

Total ICU stay (days) 7.1 (4.6) 0.13 Infection 5 (38.5) 23 (57.5) 0.58
Total LOS (days) 12.8 (6.7) 0.07 Intubation 2 (15.4) 19 (47.5) 0.59
Infection 3.6 (2.3) 0.11 Pressors 3 (23.1) 7 (17.5) 0.5
Intubation 1.2 (1.5) 0.42 HD/CRRT 2 (15.4) 2 (5) 0.38
Vasopressor use 1.1 (2.3) 0.62 Ocular 2 (15.4) 14 (35) 0.1

Please cite this article in press as: C.H. Pham, et al., Combination therapy: Etanercept and intravenous immunoglobulin for the acute
treatment of Stevens-Johnson syndrome/toxic epidermal necrolysis, Burns (2019), https://doi.org/10.1016/j.burns.2018.12.018
JBUR 5741 No. of Pages 5
4 burns xxx (2019) xxx –xxx
had a SCORTEN of 4 (expected 58.3% mortality), 70% TBSA
involvement, had a six-day delay to presentation to the burn
unit, renal failure with CRRT, and passed from complications
from sepsis. Possible explanations for their poor outcomes
may be explained by recent data showing that in patients with
SJS/TEN, septicemia and renal failure are independently
associated with an increased risk of death by 30 (adjusted
odds ratio=30.45, P<0.05) and 300 (adjusted odds ratio=300.28,
P<0.05) [26]. In addition, patient YY also received multiple
doses of high-dose corticosteroids at an outside hospital,
which has been controversially associated with significantly
higher mortality in SJS/TEN patients [5].
SJS/TEN has been associated with class I HLA alleles and
exhibits a drug-specific, class I restricted T cell response [27];
however, despite advances in the understanding of the
pharmacogenomics of SJS/TEN, its precise pathophysiology
remains unclear. Strong evidence suggests that granulysin is
the primary cytotoxic mediator in the pathophysiology of SJS/
TEN [28] and is released by CD8+ T cells, natural killer T cells,
and natural killer cells. TNF-alpha has been previously shown
to activate granulysin promoter activity [29]. Therefore,
etanercept’s therapeutic mechanism in SJS/TEN may be
through reductions in granulysin levels in serum and blister
fluid [30].
Through a similar mechanism, cyclosporine — which
reduces levels of CD4+/D8+ T cells in the epidermis and
provides concurrent inhibition of TNF-alpha has also
demonstrated significant reductions in SJS/TEN mortality
(SMR=0.320, 95% CI 0.119–0.552, P=0.002) [31].
The most convincing data supporting the use of etanercept
in treating SJS/TEN comes from the TSCAR Consortium [30],
which published a 96 patient randomized controlled trial
comparing etanercept vs. corticosteroids. The TSCAR Consor-
tium demonstrated that etanercept-treated patients had
lower observed rates of mortality (when compared to
SCORTEN) and faster time-to-healing when compared to
patients receiving steroids [30] Although our study was smaller
than the TSCAR Consortium study [30], our cohort had more
severe disease presentations (3 vs. 1.9, SCORTEN) and was
treated with IVIg and supportive care instead of corticosteroids
and supportive care.
Some have questioned the efficacy of TNF-alpha inhibitors
in the treatment of SJS/TEN due to a prior RCT showing an
increased mortality with the use of thalidomide, a potent TNF-
alpha inhibitor [32]. TNF-alpha levels in patients treated with
thalidomide tended to be paradoxically higher than the
placebo group, possibly explaining the increased mortality;
however, Wang et al. [30] showed that there were significant
reductions in TNF-alpha levels in the serum and blister fluid of
SJS/TEN patients.
Our current algorithm is to provide weight-based IVIg for
three days and a one-time subcutaneous injection (50mg) of
etanercept on a case-by-case basis, pending contraindications
such as active tuberculosis infection, sepsis, or a history of
chronic viral hepatitis. While others have documented the use
of etanercept for SJS/TEN [16–21] and the associated outcomes,
this is the largest published study to date. In addition, we were
able to use a large (N=40) previously published [3] cohort at the
same institution to compare outcomes before and after
the routine adoption of etanercept to our treatment algorithm
Please cite this article in press as: C.H. Pham, et al., Combination therapy: Etanercept and intravenous immunoglobulin for the acute
treatment of Stevens-Johnson syndrome/toxic epidermal necrolysis, Burns (2019), https://doi.org/10.1016/j.burns.2018.12.018
to draw comparisons between outcomes while controlling for
variation in institutional practices and patient population.
Limitations of this study include the retrospective design
and small sample size, which limit our conclusions to the
quality of documentation and statistical power. Also, although
one meta-analysis has argued no survival benefit when IVIg is
compared to supportive care (OR=0.99, 95% CI 0.64, 1.54) [7], we
noted that the meta-analysis was biased due to lack of
randomization, blinding, and possible publication bias in the
included studies. We continue to use IVIg in our protocol
because of historically positive outcomes at our institution [3].
In conclusion, our study provides new insights into the
combination therapy of etanercept and IVIg in SJS/TEN
patients with severe disease. Etanercept can be used on a
case-by-case basis and patients should be screened prior to use
for contraindications such as latent tuberculosis infection or
active infection [33,34].
Funding sources
None.
Conflict of interest
We wish to confirm that there are no known conflicts of
interest associated with this publication and there has been no
significant financial support for this work that could have
influenced its outcome.
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