Journal of Plastic, Reconstructive & Aesthetic Surgery (2016) 69, 733e735
EDITORIAL
Toxic epidermal necrolysis: The past, the
guidelines and challenges for the future
Toxic epidermal necrolysis (TEN) is one of the most
extraordinary diseases that dermatologists face in terms of
morbidity, mortality and sequelae. It has also been a major
challenge for research to elucidate its mechanisms. It is
more than an acute skin failure; it is a systemic disease that
requires a multidisciplinary approach. This challenge has
been taken up and resulted in collaboration between der-
matologists, plastic surgeons, burn surgeons, intensivists and
other specialists. Indeed, during the past decade, major
advances have been made in diagnosing Stevens-Johnson
syndrome (SJS) and TEN, managing their manifestations and
identifying both their pathogenesis and at-risk populations.
Since the report in 1956, by Alan Lyell,1 a Scottish
dermatologist, it has become clear that these two diseases
SJS and TEN are variants of epidermal necrolysis and part of
a disease continuum. This can be defined by the extent of
body surface area skin detachment: <10% is classified as
SJS,
30% as TEN and in between as SJS/TEN overlap. In
this editorial we will refer to SJS/TEN for the whole spec-
trum. Although SJS/TEN is generally considered to be a
drug-induced disease, in approximately 30% of cases, no
causative drug is identified; in 15% of these, drug re-
sponsibility is deemed unlikely.2 Mycoplasma pneumoniae
infection has been associated with SJS/TEN in children.3
The characteristic lesions and their evolution over a
limited time period (7e10 days) are well detailed in the
new UK guidelines published in this issue of JPRAS and BJD.
Accurate diagnosis relies on a broad spectrum of clinical
signs/symptoms and histological test: skin biopsy confirm-
ing full-thickness epidermal necrosis and a negative direct
immunofluorescence test are mandatory to exclude other
possible diagnoses.
SJS/TEN is considered to be a drug hypersensitivity
reaction mediated by cytotoxic T cells. However, a new
pathophysiological hypothesis has emerged, known as
“the altered peptide repertoire model”. In this concept,
the drug binds non-covalently within the binding pocket of
DOI of original article: http://dx.doi.org/10.1016/
j.bjps.2016.01.034.
http://dx.doi.org/10.1016/j.bjps.2016.04.016
1748-6815/ª 2016 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.
the major histocompatibility complex (MHC), leading to
alteration of both the chemistry of the binding cleft and
of the self-peptide repertoire. This “new self-peptide”
presentation then leads to cytotoxic T cell activation.4
Genetic predisposition has been reported in relation to
specific human leucocyte antigen (HLA) -A, B or C alleles.
First demonstrated in countries with a high prevalence of
one specific allele and few ethnic groups, high (100%)
correlations were established between HLA-B*15:02 and
carbamazepine-induced SJS/TEN, and HLA-B*58:01 and
allopurinol-induced SJS/TEN.5 European studies, however,
failed to demonstrate such an association. Adding to the
complexity of mechanism, recent genome wide associa-
tion studies identified ABC transporter and proteasome
pathways as potentially implicated in non drug-specific
SJS/TEN.6 Drug-specific cytotoxic cells are probably not
the sole effector mechanisms of epidermal necrolysis and
their impact may be amplified by massive production of
cell death mediators, altered anti-apoptotic pathways in
target cells and/or defective negative regulation of drug-
specific immune reactions. Epidermal cell death results
from necrosis and massive T cell-mediated apoptosis via
three described pathways: FaseFas ligand interaction,
perforin-granzyme B and granulysin.7
Once the diagnosis is confirmed, culprit drug identifica-
tion and its early withdrawal are mandatory and improve
the prognosis.8
It is a moot point whether all patients with >10% body
surface area (BSA) epidermal loss should be admitted to a
burn centre or intensive care unit (ICU). Burn centres in the
UK are widely spaced apart, which can necessitate moving
patients long distances from family and local physicians
who have knowledge of their medical conditions. In addi-
tion, ICU care is an expensive and scarce resource, usually
reserved for those who require organ support. However,
underlying this recommendation is recognition of the un-
predictable nature of the disease and its potential for rapid
progression. Recent studies have failed to show an associ-
ation between %BSA and mortality, with one burn centre
reporting the highest mortality in the SJS/TEN overlap
group.9,10
734
Increased mortality is described in patients with under-
lying malignancies and several factors contribute to the
poor prognosis, including malnutrition, cancer type and
chemotherapy. Applied at hospitalisation, SCORTEN (a
prognostic score built on seven independent variables),
successfully predicts day-3 mortality and the individual risk
of death for SJS/TEN series.11
These guidelines were prepared by a multidisciplinary
group and consideration is given to the different ap-
proaches to skin management. Detached epidermal sheets
may be retained to act as a biological wound dressing,
with many dermatologists favouring this method. In the
instance of extensive necrotic tissue with the potential for
infection, a more pro-active approach can be beneficial.
This involves gentle wound cleansing to remove loose
debris, and application of simple or biological dressings to
protect the underlying dermis. Sepsis is the main cause of
mortality in SJS/TEN and adequate wound care is impor-
tant to prevent wound colonisation by pathogenic organ-
isms.10,12,13 In addition to protecting against infection,
wound dressings improve patient comfort and reduce
analgesia requirements.
The guideline advises caution on use of silver dressings
for extensive areas. Silver is absorbed from dressings or
creams applied to open wounds, and subsequently excreted
in the bile and urine. There is a lack of evidence that silver
absorbed from dressings used for a limited time period
causes any clinical problems.14
The many aspects of supportive care are well detailed in
the guidelines, whilst with regard to specific treatments,
the authors noted the lack of evidence-based medicine
available. The lack of large randomised-controlled trials
(RCTs) comparing treatment strategies reflects the rarity of
the disease. Several immunosuppressant and immunomod-
ulatory treatments have been reported as potentially
beneficial. Indeed, the current debate is well summarised;
nevertheless, we will attempt to combine the conclusions
with our own experience. There has only been one pub-
lished RCT in patients with TEN, and this showed an excess
mortality for treatment with thalidomide versus placebo.15
Two conclusions can be drawn; 1) thalidomide is delete-
rious during TEN and 2) despite the rarity of the disease,
RCTs are possible. In our experience, corticosteroids do not
significantly impact mortality. In the Burn Centres in Bir-
mingham, UK, IVIg is used for TEN, supported by a retro-
spective study of 21 patients with a mean 44% BSA skin loss
(3 deaths in the treatment group compared to a SCORTEN-
predicted mortality of 5).13 Although immunosuppressive
therapy has not emerged as optimal for SJS/TEN compared
to supportive care, in the Dermatological Referral Centre of
Créteil (Grand Paris Region) cyclosporine is still used. In a
published trial, cyclosporine16 prevented skin-detachment
progression in SJS/TEN, with only 38% of patients devel-
oping progressive disease, as opposed to 65% of those in the
open IVIg trial. No deaths occurred, although SCORTEN
predicted three. This potential benefit of cyclosporine on
mortality in comparison to IVIg was also established in
single centre study of 71 patients. Acute-stage mortality
ranged from at least 10% for SJS to 39% for TEN, with overall
in-hospital mortality of 22%.
After the acute episode, follow-up for physical and
psychological sequelae is important. Post etraumatic stress
Editorial
disorder (PTSD) was a major concern for our patients in the
past. Specific management, with the use of anxiolytics both
during and after the acute stage, has dramatically
decreased the long-term risk.
Facing the challenges of the future, pathophysiological
research should focus on other genetic predictive factors,
especially in patients with non-drug causation, with the
aim of improving prevention. For example, supported by
the results of extensive HLA-B*15:02 screening in Taiwa-
nese neurology clinics, the FDA recommends genetic
testing before prescribing carbamazepine to most pa-
tients of Asian ancestry. Such HLA-screening is only
relevant for a few alleles in specific populations. Tools to
ascribe a drug’s responsibility for the disease are limited
and none of the existing tests have sufficient sensitivity
and specificity to rule out a potential culprit drug when
negative, enabling its re-challenge. This should be
improved. With regard to treatment, it has been shown
that a RCT is possible. In the future, Granulocyte-
macrophage colony-stimulating factor (GMeCSF) may be
relevant, as some data suggest an effect on SJS/TEN re-
epithelialisation via T-regulatoryecell mobilisation,
expansion of tolerogenic myeloid precursors, immature
dendritic cell mobilisation or enhanced cytolytic func-
tions of NK-T cells. In this rare disease only international
co-operation and multicentre trials could give sufficient
power for such studies.
The guideline development group included a patient
representative, underlining the role of lay organisations in
providing valuable emotional and practical support for
survivors, as well as education. In France, ‘Amalyste’ has
contributed to improving SJS/TEN outcomes, knowledge of
sequelae and also compensation through designated funds.
In conclusion:
 These excellent guidelines are the culmination of
several years of hard work and co-operation between
specialists. Both patients and professionals should
acknowledge their huge contribution towards the un-
derstanding and management of SJS/TEN.
 The lack of strong evidence available (mostly level 3 and
4) necessitated that many recommendations are based
on a consensus of expert opinion. This allows for local
adaptations and variations to be implemented within
individual hospitals.
 Our aim should be that by the time the guidelines are
revised in 2021, research is available to impact on both
prevention and evidence ebased treatment of this
potentially devastating condition.
Conflict of interest
Novartis (Principal Investigator), Pierre Fabre Dermatologie
(Consultant).
Acknowledgements
We thank Olivier Chosidow and Naiem Moiemen for their
helpful comments.
Editorial
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Pierre Wolkensteina
Department of Dermatology, Hôpital Henri-Mondor,
AOHP, UPEC, Créteil, France
Service de dermatologie, GHU Henri Mondor,
51 Avenue du Maréchal de Lattre de Tassigny,
94010 Créteil Cedex, France
E-mail address: pierre.wolkenstein@aphp.fr
(P. Wolkenstein)
Yvonne T. Wilson*
The Burn Centre,
Birmingham Children’s Hospital and
University Hospital Birmingham,
Steelhouse Lane, Birmingham B4 6NH, UK
*Corresponding author. Tel.: þ44 121 333 8963.
E-mail address: yvonne.wilson@uhb.nhs.uk (Y.T. Wilson)
30 March 2016
a
Tel.: þ33 (0)149814461.