Clinic Rev Allerg Immunol (2018) 54:147–176
https://doi.org/10.1007/s12016-017-8654-z
Current Perspectives on Stevens-Johnson Syndrome and Toxic
Epidermal Necrolysis
Marianne Lerch 1 & Carlo Mainetti 2 & Benedetta Terziroli Beretta-Piccoli 3
Thomas Harr 4
Published online: 29 November 2017
# Springer Science+Business Media, LLC 2017
Abstract Stevens-Johnson syndrome (SJS) and toxic epider-
mal necrolysis (TEN) are considered a delayed-type hypersen-
sitivity reaction to drugs. They represent true medical emergen-
cies and an early recognition and appropriate management is
decisive for the survival. SJS/TEN manifest with an Binfluenza-
like^ prodromal phase (malaise, fever), followed by painful
cutaneous and mucous membrane (ocular, oral, and genital)
lesions, and other systemic symptoms. The difference between
SJS, SJS/TEN overlap, and TEN is defined by the degree of
skin detachment: SJS is defined as skin involvement of < 10%,
TEN is defined as skin involvement of > 30%, and SJS/TEN
overlap as 10–30% skin involvement. The diagnosis of differ-
ent degrees of epidermal necrolysis is based on the clinical
assessment in conjunction with the corresponding histopathol-
ogy. The mortality rates for SJS and TEN have decreased in the
last decades. Today, the severity-of-illness score for toxic epi-
dermal necrolysis (SCORTEN) is available for SJS/TEN sever-
ity assessment. Drugs with a high risk of causing SJS/TEN are
anti-infective sulfonamides, anti-epileptic drugs, non-steroidal
anti-inflammatory drugs of the oxicam type, allopurinol, nevi-
rapine, and chlormezanone. Besides conventional drugs, herbal
remedies and new biologicals should be considered as causative
agents. The increased risk of hypersensitivity reactions to
* Thomas Harr
Thomas.Harr@hcuge.ch
1
Allergy/Dermatology Unit, Department of Internal Medicine,
Kantonsspital Winterthur, Winterthur, Switzerland
2
Department of Dermatology, Bellinzona Regional Hospital,
Bellinzona, Switzerland
3
Epatocentro Ticino, Lugano, Switzerland
4
Unité d’allergologie, Service d’immunologie et d’allergologie,
Hôpitaux Universitaires de Genève HUG, Genève, Switzerland
&
certain drugs may be linked to specific HLA antigens. Our
understanding of the pathogenesis of SJS/TEN has improved:
drug-specific T cell-mediated cytotoxicity, genetic linkage with
HLA- and non-HLA-genes, TCR restriction, and cytotoxicity
mechanisms were clarified. However, many factors contribut-
ing to epidermal necrolysis still have to be identified, especially
in virus-induced and autoimmune forms of epidermal
necrolysis not related to drugs. In SJS/TEN, the most common
complications are ocular, cutaneous, or renal. Nasopharyngeal,
esophageal, and genital mucosal involvement with blisters, ero-
sions as well as secondary development of strictures also play a
role. However, in the acute phase, septicemia is a leading cause
of morbidity and fatality. Pulmonary and hepatic involvement is
frequent. The acute management of SJS/TEN requires a multi-
disciplinary approach. Immediate withdrawal of potentially
causative drugs is mandatory. Prompt referral to an appropriate
medical center for specific supportive treatment is of utmost
importance. The most frequently used treatments for SJS/
TEN are systemic corticosteroids, immunoglobulins, and cyclo-
sporine A.
Keywords Stevens-Johnson syndrome . Toxic epidermal
necrolysis . Erythema multiforme . Drug reaction .
Intravenous immunoglobulins
Abbreviations
ACSR Anti-folate cytotoxic skin reaction
AGEP Acute generalized exanthematous pustulosis
ALDEN Algorithm for assessment of drug causality
in epidermal necrolysis
Anti PD-L1 Anti programmed death-ligand 1
APACHE Acute physiology and chronic health
evaluation
BSA Body surface area
148 Clinic Rev Allerg Immunol (2018) 54:147–176

BSLE Bullous systemic lupus erythematosus TEN with and without spots. Bullous EM is defined as skin
CBZ Carbamazepine detachment of < 10% with typical and raised atypical targets,
CsA Cyclosporine A but without spots. The difference between SJS, SJS/TEN
DIHS Drug-induced hypersensitivity syndrome overlap, and TEN is defined by the degree of skin detachment.
DRESS Drug reaction with eosinophilia and systemic Whereas SJS is defined as skin involvement of < 10%, TEN is
symptoms defined as skin involvement of > 30% (TEN without spots
EBA Epidermolysis bullosa acquisita > 10%), and SJS/TEN overlap as 10–30% skin involvement
EM Erythema multiforme (WAO 2014). SJS/TEN overlap and TEN show no typical
FACS Fluorescence-activated cell sorting target lesions, but flat atypical target lesions that are absent
FasL Fas ligand in bullous EM and spots [4]. In contrast, the subgroup of TEN
GBFDE Generalized bullous fixed drug eruption without spots shows > 10% of detachment, without typical or
GSTM1 Glutathione S-transferase Mu 1 atypical target lesions (Table 1).
GvHD Graft versus host disease According to the World Allergy Organizations (WAO) def-
HLA Human leukocyte antigen inition of 2014, SCAR includes the following: SJS, SJS/TEN,
ICNARC Intensive Care National Audit & Research TEN, and drug-induced hypersensitivity syndrome/drug reac-
Center tion with eosinophilia and systemic symptoms (DRESS).
IVIG Intravenous immunoglobulins The clinical pattern of EM differs from SJS/TEN as de-
LABD Linear IgA bullous dermatosis scribed by Auquier-Dunant et al. It is characterized by local-
LTT Lymphocyte transformation test ized typical target lesions with distinct acral distribution and
MIEN Methotrexate-induced epidermal necrolysis skin involvement of less than 10% [5].
MRR Mortality risk ratio Today, SJS/TEN is considered a delayed-type hypersensitiv-
NK cells Natural killer cells ity reaction to drugs. Pichler further subdivided Coombs and
NSAIDs Nonsteroidal anti-inflammatory drugs Gell type IV reactions into several subtypes [6]. Whereas in
PCR Polymerase chain reaction type IV-a, monocytes and in type IV-b eosinophils are implicat-
SCORTEN Severity-of-illness score for toxic epidermal ed, type IV-c typically refers to cytotoxicity of drug-specific T
necrolysis cells with clinical correlation to SJS/TEN. Type IV-d implicates
SJS Stevens-Johnson syndrome activation of neutrophils and clinically correlates with acute
SMR Standardized mortality rate generalized exanthematous pustulosis (AGEP).
SMX/TMP Sulfamethoxazole/trimethoprim
SSSS Staphylococcal scalded skin syndrome
TBSA Total body surface area
TEN Toxic epidermal necrolysis Epidemiology
TNF Tumor necrosis factor
TRAIL TNF-related apoptosis-inducing ligand SJS/TEN is a rare disease and usually, but not exclusively, rep-
TWEAK TNF-like weak inducer of apoptosis resents a drug reaction. The reported overall incidence of TEN in
VBDS Vanishing bile duct syndrome a Greater Seattle Area based study conducted in the 70s and 80s
was 0.5 per million person-years [7]. In patients taking medica-
tions, the incidence increased to 1.8 cases per million person-
Introduction years for SJS, and to 9.0 for TEN. A newer USA-based study
analyzing nationwide inpatient records from 2009 to 2012 calcu-
At the beginning of the last century, two cases of skin detach- lated an incidence per million inhabitants of 8.61 to 9.69 for SJS,
ment with mucosal involvement were published by Mason 1.46 to 1.84 for SJS/TEN, and 1.58 to 2.26 for TEN [8]. In SJS,
Stevens and Chambliss Johnson, two American pediatricians SJS/TEN, and TEN, an association with hematological malig-
[1]. Toxic epidermal necrolysis (TEN) was first described by nancies and certain infections (HIV, fungal infections) as well as
Alan Lyell in 1956 [2]. In 1917, two French physicians de- liver and kidney disease, was found. However, a clear association
scribed an exanthem with acral distribution of typical target with central nervous system cancer, Mycoplasma infection, in-
lesions. This syndrome, known as Fiessinger and Rendu syn- fectious hepatitis, vision impairment, lupus erythematosus, and
drome, resembles erythema multiforme rather than Stevens- acute kidney injury could not be established for SJS/TEN or
Johnson syndrome (SJS) [3]. The first consensus-based defi- TEN [8]. Mortality rate of SJS, SJS/TEN, and TEN was 4.8,
nition of severe cutaneous adverse reactions (SCAR) was 19.4, and 14.8%, respectively. Predictors of mortality were age,
attempted in 1993 by Bastuji-Garin et al [4]. They classified pre-existing comorbidities, hematological malignancy, septice-
severe bullous skin reactions into five subgroups, namely bul- mia, pneumonia, tuberculosis, and renal failure. Interestingly, in
lous erythema multiforme (EM), SJS, SJS/TEN overlap, and this study, mortality rate was not influenced by skin infections.
Clinic Rev Allerg Immunol (2018) 54:147–176
Table 1 Classification of severe bullous skin reactions
Proposed classification of cases in the spectrum of severe bullous EMa
Classification Bullous EM SJS
Detachment < 10% < 10%
Typical targets Yes – –
Atypical targets Raised Flat
Spots – Yes
Adapted from Bastuji-Garin S et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.
Arch Dermatol 1993; 129(1): 92–96
a
EM indicates erythema multiforme; SJS, Stevens-Johnson syndrome; and TEN, toxic epidermal necrolysis
In a pediatric population (20% of hospitalizations in the
USA) studied by the same group, SJS was reported to have
an incidence of 5.3, SJS/TEN of 0.8, and TEN of 0.4 cases per
million age-adapted population [9]. Malignancy, septicemia,
bacterial infection, and epilepsy were identified as risk factors
for mortality in this group. In a multi-center study based in the
greater Sao Paolo area (Brazil), SJS and SJS/TEN were ob-
served in 5 of 852 female pediatric patients with childhood-
onset systemic lupus erythematosus (0.6%) [10]. Mortality
rates in children with TEN are lower than in adults ranging
from 0 to 7.5% [11] compared to an overall mortality in adults
of approximately 30% [12].
The incidence of SJS/TEN in a population-based European
study (Western Germany and Berlin) in 1990–1992 was 1.89
per million inhabitants [13]. In Northern Italy, SJS/TEN had
an overall incidence of 1.4 cases per million inhabitants [14].
The medical insurance review system database of South
Korea identified 938 SJS and 229 TEN cases from 2010 to
2013, with a calculated incidence rate per million inhabitants
of 3.96 to 5.0 SJS, and 0.94 to 1.54 TEN cases. No significant
increase in annual incidence during the study period was ob-
served. However, patients older than 70 years had the highest
risk to develop SJS and TEN [15]. On a single drug level,
based on a systemic review of 122 randomized trials including
18,698 patients, a risk to develop SJS/TEN after use of
lamotrigine of 0.04% (8 of 18,698 patients) was calculated
by Bloom et al. [16]. The overall incidence in a UK-based
epidemiological study was 5.76 SJS/TEN cases per million
person years, with 551 SJS/TEN patients reported from
1995 to 2013. Children aged 1–10 years and patients over
80 years had the highest risk to develop SJS/TEN [17]. The
same study identified comorbidities that are associated with a
higher risk to develop SJS/TEN, considering that drug intake
could be one of the confounding factors. As an autoimmune/
collagen vascular disease, lupus erythematosus was associated
with SJS/TEN with an odds ratio of 16.0. Typically, these
patients developed SJS/TEN within the first 3 months of drug
intake. Active cancer was also identified as a risk factor for
SJS/TEN (odds ratio 2.01), whereas in non-active cancer, the
149
Overlap SJS-TEN TEN
With spots Without Spots
10–30% > 30% > 10%
– –
Flat Flat –
Yes Yes –
risk of SJS/TEN depended on the underlying malignancy. The
highest risk was seen in bone and ovarian cancer (odds ratio
9.66), hematologic malignancy (odds ratio 9.46), and to a
lesser extent in cancer of the nervous system (odds ratio
2.86), and cancer of the respiratory tract (odds ratio 2.67). In
inactive cancer of the breast as well as cancers of the colon,
prostate and skin, no increased risk was reported. A higher
incidence rate of SJS/TEN was also attributed to acute kidney
disease (odds ratio 6.00). These patients had a significant risk
to develop SJS/TEN within the first 84 days (odds ratio 4.65)
when newly on anti-epileptic drugs. After this period, the risk
decreased to an odds ratio of 1.44. Similar findings were seen
in patients using allopurinol, where the risk to develop SJS/
TEN was highest within the first 84 days (odds ratio 20.48)
dropping sharply afterwards to an odds ratio of 1.55.
An independent risk factor for SJS/TEN is HIV infection.
The risk to develop SJS/TEN was increased a 100-fold in
HIV-positive patients reported in the Ontario HIV treatment
network [18]. In another patient collective at the San
Francisco General Hospital, this higher incidence rate could
be confirmed in patients with or without active anti-retroviral
therapy (HAART). Sulfamethoxazole/trimethoprim (SMX/
TMP) treatment was the most frequent drug inducing TEN
in these patients [19]. In a South African study of SJS/TEN,
HIV infection was shown to be the major factor associated
with a higher risk of fatal outcome (odds ratio 6). The highest
risk was found in patients with HIV/tuberculosis co-infection
(odds ratio 8.5) [20].
A retrospective cross-sectional study conducted at the
Kenyatta National Hospital from 2006 to 2016 identified
150 patients with severe cutaneous disease, whereof almost
half the patients were between 21–40 years of age, with a
female predominance. In 95% of all SJS/TEN cases, drugs
were the main inducers, most frequently sulfonamides and
nevirapine, HIV being the most frequently identified infection
in these patients [21].
Maternofetal outcome was studied in 22 HIV-infected
women in a South African study. In this study, almost all
SJS/TEN cases—SJS being more frequent—were attributed
150
to nevirapine during pregnancy. Whereas all women survived,
two fetuses died during pregnancy, showing no signs of SJS/
TEN. Also, 6 weeks after birth, all babies postnatally treated
with nevirapine were HIV-negative and did not show any
signs of SJS/TEN [22].
Diagnosis
The diagnosis of different degrees of epidermal necrolysis is
based on the clinical assessment in conjunction with the cor-
responding histopathological findings of subepidermal blis-
ters with widespread necrosis and apoptotic keratinocytes as-
sociated with minimal lymphocytic inflammatory infiltrate.
All three forms of epidermal necrolysis are characterized by
widespread blister formation on erythematous skin, and flat,
atypical target lesions. In almost all cases, mucous membranes
are involved. The degree of involved skin is calculated based
on the total of all blisters, partially or completely detached
skin, and Nikolsky positive, detachable areas. For the calcu-
lation of the involved body surface area (BSA) only
undetached and non-detachable erythematous or violet zones
are not included. By definition, in SJS < 10%, in SJS/TEN
overlap 10–30% and in TEN (formally known as Lyell syn-
drome) > 30% of BSA is involved [4] (Fig. 1). The typical
histological finding is massive epidermal necrosis (including
all layers of the epidermis) and a sparse dermal inflammatory
infiltrate [23] (Fig. 2). The distinction between SJS, SJS/TEN,
and TEN based on histopathological findings is not possible
[24, 25]. Systemic involvement is difficult to distinguish from
secondary complications due to SJS/TEN.
Fig. 1 Clinical presentation of
TEN. a Dark purple macular
lesions on trunk. b Incipient
blister formation on
erythematous/violet zones and
detachable skin. c Extensive skin
detachment. d Oral mucosal
involvement
Clinic Rev Allerg Immunol (2018) 54:147–176
Differential Diagnosis
In the differential diagnosis of SJS/TEN, erythema
exsudativum multiforme majus, autoimmune bullous dis-
eases (e.g., linear IgA dermatosis, epidermolysis bullosa
acquisita), autoimmune diseases (e.g., bullous lupus erythe-
matosus), staphylococcal scalded skin syndrome (SSSS), and
generalized fixed bullous drug eruption as well as acute gen-
eralized exanthematous pustulosis (AGEP) should be consid-
ered. The differential diagnosis of overlap diseases such as
AGEP/epidermal necrolysis and combinations with pre-
existing diseases, like systemic lupus erythematosus, may be
problematic as they can be clinically indistinguishable from
SJS/TEN.
Today, EM is considered a different disease from all forms
of epidermal necrolysis (SJS, SJS/TEN, TEN). EM typically
has an acral distribution and is characterized by typical and/or
raised atypical targets. In EM, skin detachment is less than
10% BSA by definition [4]. There are two variants of EM,
namely EM minus with no or just one mucosal site involved,
and EM majus with two or more mucosal sites involved
(Fig. 3). The involvement of a single or no mucosal site would
be very atypical for SJS. As compared to epidermal
necrolysis, in EM, not only the clinical presentation but also
the histopathological findings differ [23]. In EM, there is a
dense infiltrate at the dermoepidermal interface consisting
mainly of lymphocytes and histiocytes. Also, satellite cell ne-
crosis and continuous subepithelial necrosis can be seen.
Recurring EM is seen in approximately 30% of cases, whereas
in epidermal necrolysis recurrence is a rarity (3–4%), unless
the culprit drug is re-administered [5]. While EM is often
associated with Herpes simplex virus (HSV) infection, only
Clinic Rev Allerg Immunol (2018) 54:147–176
Fig. 2 Histopathological findings in TEN. a Extensive subepidermal
hemorrhage, hemosiderin deposition, completely detached necrotic
epidermis without significant inflammatory infiltrates. H&E,
magnification ×50. b Completely detached necrotic epidermis. H&E,
magnification ×400. c Sparsely adhering necrotic epidermis in border
area. H&E, magnification ×400
a minority of SJS cases are related to HSV infection.
According to a large prospective study, SJS/TEN overlap
and TEN were not associated with HSV infection [5]. Wetter
et al. found 23% of patients to have a probable HSV associa-
tion and 17% of patients with a possible relevance of HSV as
causing agent in recurrent EM [26]. Furthermore, the authors
identified Mycoplasma pneumoniae, Candida, and Hepatitis
C virus in one patient each out of 48 patients with recurrent
EM. In this study, only one patient was found to have drug-
associated (acetaminophen) recurrent EM. In several publica-
tions Mycoplasma pneumoniae, also known to cause EM in
children, was identified as the most likely causative infectious
agent [27, 28]. Fuchs syndrome is thought to be a variant of
EM, characterized by isolated enanthema and erosions of
151
potentially all mucosal membranes, such as the eyes as well
as the oropharyngeal and genitourinary regions, without typ-
ical skin lesions.
Based on their clinical presentation, certain autoimmune
bullous diseases can be indistinguishable from SJS/TEN.
Among others, linear IgA bullous dermatosis (LABD) can
have typical features of SJS/TEN (Fig. 4) [29–31].
Histopathologically, LABD is characterized by linear IgA de-
positions at the dermoepidermal interface with a dense neu-
trophil infiltrate and sub-epidermal blistering, clinically man-
ifesting as widespread blistering and erosive cutaneous and
mucosal lesions [29–31]. In LABD, there are spontaneous/
idiopathic forms and drug-associated cases. Chanal et al.
showed that in drug-induced LABD, a SJS/TEN-like clinical
pattern is found more often than in spontaneous/idiopathic
LABD [32]. Vancomycin and phenytoin were identified as
the major cause for drug-induced LABD from 1975 to 2013
[33], though other drugs like piperacillin/tazobactam as well
as verapamil were also recently linked to LABD [34, 35].
Also, a case of epidermolysis bullosa acquisita (EBA) re-
sembling TEN was described, where diagnosis could only be
established based on indirect immunofluorescence on salt-split
skin and immunoblots [36]. In addition, paraneoplastic pemphi-
gus [37] and pemphigus vulgaris can also mimic TEN [38].
A further diagnostic challenge is the differentiation between
SJS/TEN and bullous systemic lupus erythematosus (BSLE). In
BSLE as in EBA, autoimmunity to type VII collagen can be
found. Here, diagnosis can also only be made by clinical history,
histopathological analysis, direct- and indirect immunofluores-
cence, and serology [39]. However, simultaneous presentation
of lupus erythematosus with other autoimmune bullous diseases
such as pemphigus, EBA, LABD, dermatitis herpetiformis, and
bullous pemphigoid have to be considered [40].
SJS/TEN may be the initial manifestation of lupus erythe-
matosus (LE) without previous intake of relevant drugs.
Therefore, LE is thought to be the cause of SJS/TEN in some
patients [41]. This leads to the assumption that LE-associated
TEN might be a more severe form of Rowell`s syndrome
(erythema multiforme-like lesions associated with lupus ery-
thematosus) [42]. TEN-like cutaneous lupus in pediatric pa-
tients with SLE is a rare entity and can be difficult to differ-
entiate from drug-induced TEN [43].
Clinically and histologically, severe forms of graft versus
host disease (GvHD) can resemble TEN. In both entities,
CD8+ T cells are the predominant inflammatory cells found
in the blister fluid [44], though in GvHD, dermal infiltrates
were shown to be denser and to have higher counts of CD4+ T
cells [45]. In a review of 152 allogeneic bone marrow recipi-
ents, nine patients with fatal course were retrospectively diag-
nosed with TEN [46].
Staphylococcal scalded skin syndrome (SSSS) is a blister-
ing disease with skin detachment and frequent mucous mem-
brane involvement that is induced by Staph. aureus producing
152 Clinic Rev Allerg Immunol (2018) 54:147–176

Fig. 3 Erythema exsudativum

multiforme majus. a Oral mucosal
involvement. b Dark red purple
macular lesion on the left hand. c
Red macular target lesion on the
left foot. d Genital mucosal
involvement

exfoliative toxins (Fig. 5) [47, 48]. Although SSSS is mainly
seen in children under three years, adults may sometimes be
affected [49]. Typically, SSSS is not associated with drug use.
Histologically, an intraepidermal cleavage directly below the
corneal layer, without the typical necrotic keratinocytes seen
in TEN, is found [50]. Miyashita et al. suggested the use of
dermoscopy for the initial clinical evaluation to distinguish
SSSS from TEN [51], since SSSS shows an intact epidermis
with discrete leachate in acute detached skin areas as com-
pared to TEN.
Generalized bullous fixed drug eruption (GBFDE) typical-
ly shows clearly demarcated deep-red skin lesions with or
without blisters, or alternatively pigmented skin areas, with
occasional mucous membrane involvement (Fig. 6).
Conventional histological evaluation shows more dermal
CD4+ T cells in GBFDE than in TEN. GBFDE and TEN
are difficult to distinguish as both can show basal
vacuolisation and apoptotic keratinocytes. However, in
GBFDE dermal eosinophils, melanophages as well as a higher
count of CD4+ T cells are found [52].
Acute generalized exanthematous pustulosis (AGEP) is
characterized by widespread, sometimes more localized,
non-follicular pustules. Typically, the pustular lesions show
a diffuse distribution pattern (Fig. 7). Occasionally,
vesicular-bullous lesions can be seen. Patients with AGEP
usually have peripheral neutrophilia. Histology shows typical

Fig. 4 Linear IgA bullous

dermatosis. a Oral mucosal
involvement. b Erythematous
macular lesions and blisters of the
left armpit region. c Blister on the
left arm
Clinic Rev Allerg Immunol (2018) 54:147–176 153

Fig. 5 Staphylococcal scalded

skin syndrome. a Perioral
erythema with superficial skin
detachment. b Fine vesicobullous
skin detachment (Nikolsky sign)
on erythema of the left armpit
region. c Superficial skin
detachment of the anal region.

subcorneal and intraepidermal pustules with a spongiform pat-
tern. Also, neutrophils and eosinophils can be found in the
dermis [53].
High doses of methotrexate may induce an anti-folate cy-
totoxic skin reaction (ACSR) that is clinically indistinguish-
able from SJS/TEN [54]. This methotrexate-induced epider-
mal necrolysis (MIEN) might sometimes be distinguished
from SJS/TEN on a histological basis. In MIEN, typically an
atrophic dermis with or without alterations, dyskeratosis, and/
or epidermal necrosis can be seen. Keratinocytes in MIEN
show reactive or atypical nuclear features [55].
Diagnostic Approach and Severity Assessment
Establishing the diagnosis of epidermal necrolysis relies pri-
marily on the clinical picture of blister formation, amount of
skin detachment, presence of atypical flat targets, and spots
with mucosal erosions. Erosions of one or more oral mucosa
surface areas are seen in more than 90% of patients with SJS/
TEN. SJS, SJS/TEN overlap, and TEN are distinguished by
the skin surface involved [4] and thus the degree of severity.
The diagnosis of SJS/TEN is confirmed by histopathological
investigation. Both SJS and TEN are characterized by

Fig. 6 Generalized bullous fixed

drug eruption induced by
sulfamethoxazole-trimethoprim.
a Erythematous macular lesions
with skin erosion on legs. b:
Erythematous macular lesions
with blisters and erosion on
palms. c Erythema and erosions
on the right arm, mimicking toxic
epidermal necrolysis
154
Fig. 7 Acute generalized
exanthematous pustulosis
induced by hydroxychloroquine.
a Macular erythema, mimicking
target lesions prior to formation of
pustular lesions on left forearm. b
Widespread, diffuse, superficial,
non-follicular pustules on erythe-
ma of thighs
complete epidermal necrosis (Bnécrose en masse^) and a usu-
ally sparse, occasionally moderate, and rarely extensive, der-
mal infiltrate [56, 57]. Reflectance confocal microscopy
shows distinct patterns and is an interesting clinical approach
for the fast diagnosis for SJS/TEN as results are available
before histopathology [58]. Direct immunofluorescence typi-
cally shows no immunoglobulin deposition, compared to au-
toimmune (blistering) diseases. However, SJS/TEN can also
be seen on top of pre-existing autoimmune blistering diseases,
or in overlap syndromes. A major prognostic factor is TBSA
(total body surface area) involvement [4]. Roujeau et al. found
a total mortality of 5 and 30% in SJS and TEN patients, re-
spectively [59]. The association of the degree of TBSA in-
volvement and mortality rate is controversial within the TEN-
group. Whereas in some publications, a correlation is found,
others do not report a direct correlation between TBSA
(> 30% in TEN) and mortality [60–63]. As epidermal
necrolysis is a multi-organ disease, TBSA alone is not suffi-
cient to predict mortality [62, 64]. Bastuji-Garin et al. devel-
oped a severity-of-illness score for toxic epidermal necrolysis
(SCORTEN) based on seven independent risk factors for epi-
dermal necrolysis, that are age > 40 years, malignancy, tachy-
cardia, initial presentation of skin detachment > 10%, serum
urea > 10 mmol/L, serum glucose > 14 mmol/L, serum bicar-
bonate < 20 mmol/L [12] (Table 2). SCORTEN represents a
specific severity-of-illness score for TEN, that was highly
accurate in predicting mortality (19.6% predicted, vs actual
20% mortality). Also, it was superior to the simplified acute
physiology score (expected mortality 9.1%, vs actual mortal-
ity 26.7%). In further studies, the good accuracy of
SCORTEN in predicting mortality was confirmed [61, 65,
66]. However, serial determination of SCORTEN within the
Clinic Rev Allerg Immunol (2018) 54:147–176
first 5 days was shown to increase its accuracy in predicting
mortality [67, 68].
As much information for the calculation of SCORTEN
may not be routinely available in all settings, Sekula et al.
developed an auxiliary score [69]. In this context, the analysis
of data of 166 patients with a complete dataset from the
EuroSCAR study, in terms of SCORTEN-predicted and actual
mortality, showed an overall predicted mortality of 17%
(SCORTEN, or severity grade: SJS, SJS/TEN overlap, or
TEN) compared to an actual mortality of 19%. Interestingly,
in patients with a low score, fatality rate was underestimated,
whereas in patients with a higher score the fatality rate was
overestimated. In patients analyzed with the auxiliary score,
an overall mortality of 22% was predicted (auxiliary score,
and severity grade: SJS, SJS/TEN overlap, or TEN), which
was comparable to actual mortality. The authors concluded
that the auxiliary score had a higher accuracy in predicting
mortality than SCORTEN. Nevertheless, due to potential re-
strictions in the data collection, they concluded that
SCORTEN is still the tool of choice. For retrospective analysis
of incomplete data the auxiliary score might however be
considered.
A newly developed pediatric SCORTEN was evaluated in
a retrospective data analysis, comparing adult SCORTEN to
pediatric SCORTEN in children without (A) or with (B) he-
matopoietic stem cell transplantation [70] (Table 2). Thereby,
the standard adult SCORTEN was a good predictor for mor-
bidity in the pediatric population, SCORTEN A and B thus
not providing an advantage over the adult SCORTEN.
A modified APACHE (acute physiology and chronic health
evaluation) II score was introduced in the clinics in 1990 [71]
as a tool to measure disease severity (Table 3). In an England,
Clinic Rev Allerg Immunol (2018) 54:147–176 155

Table 2 Comparison of current standard score for toxic epidermal necrosis (SCORTEN) and proposed pediatric SCORTENs A and B

Prognosis factor Value Significance Points

Standard SCORTEN
Age ≥ 40 yrs 1
Malignancy Present 1
Body surface area involved > 10% 1
Tachycardia ≥ 120 bpm 20% above normal heart rate 1
Serum blood urea nitrogen > 28 mg/dL 40% above normal adult upper value 1
Serum bicarbonate < 20 mEq/L 10% below normal adult lower value 1
Serum glucose > 252 mg/dL 210% above normal adult value 1
Pediatric SCORTENs A and Ba
Malignancy Present 1
Body surface area involved > 10% 1
Tachycardia < 6 mos > 162 bpm 20% above normal heart rate for age 1
6–12 mos > 144 bpm
1–6 yrs > 132 bpm
≥ 6 yrs > 120 bpm
Serum blood urea nitrogen > 25 mg/dL 40% above normal pediatric upper value 1
Serum bicarbonate < 21.6 mEq/L 10% below normal pediatric lower value 1
Serum glucose > 210 mg/dL 210% above normal pediatric value 1
Stem cell transplantationa Present 1

Adapted from Sorrell J et al. Score of toxic epidermal necrolysis predicts the outcomes of pediatric epidermal necrolysis. Pediatric Dermatology 2017;
34(4): 433–37
a
Pediatric SCORTEN evaluated without (SCORTEN A) and with (SCORTEN B) stem cell transplantation. bpm, beats per minute.

Wales, and Northern Ireland-based study on ICU patient mor-
tality EM, SJS and TEN patients as well as patients with other
dermatological diseases were analyzed. SCORTEN,
APACHE II, and ICNARC (Intensive Care National Audit
& Research Center) scores were applied in the 145 patients
included, all three scores yielding comparable results without
statistically significant difference. However, SCORTEN was
easier to apply than the more complicated APACHE II and
ICNARC scores [72].
The value of a histopathological approach to identify prog-
nostic factors remains controversial. The correlation between
better survival and sparse dermal infiltrates compared to pa-
tients with moderate to extensive dermal infiltrates demon-
strated by Quinn at al. [56] could not be reproduced by another
group [57].
Since the majority of SJS/TEN is caused by the use of
medicines, it is of paramount importance to identify the most
likely culprit drug. In this context, ALDEN, an algorithm for
assessment of drug causality in epidermal necrolysis was in-
troduced for the improved identification of drugs with very
probable, probable, unlikely, or very unlikely causality of in-
ducing SJS/TEN [73] (Table 4). The application of the
ALDEN causality score on the EuroSCAR case control anal-
ysis data to identify the causative drug yielded comparable
results for both methods. Furthermore, by comparing the
French pharmacovigilance method with the ALDEN score,
more drugs with Bprobable^ or Bvery probable^ causality of
inducing epidermal necrolysis were identified by using the
ALDEN score (69/100 vs 23/100). The authors therefore sug-
gest the ALDEN score to be used as a reference method in
SJS/TEN [73].
Granulysin is a key mediator in keratinocyte apoptosis in
SJS/TEN [74] and was found at higher serum levels in the
early stages of SJS/TEN compared to sera of controls and
patients with other drug-induced skin reactions. The
granulysin concentration was highest 2–4 days before wide-
spread skin detachment and oral involvement developed
clinically and was still clearly elevated up to 2 days after
initial skin detachment and occurrence of mucosal erosions.
Afterwards, serum levels dropped sharply on the following
days [75]. In addition, increased levels of FasL with a peak
2-4 days before clinical development of skin detachment
and mucosal erosions were found in SJS/TEN (compared
to granulysin in lower concentrations), but not in patients
with other drug reactions, by the same group. Serum FasL
levels returned to normal within five days after onset of
skin/mucosal m anifestations [ 76]. Since a rapid
immunochromatographic test is available, the authors sug-
gest granulysin to be used as predictive/diagnostic marker
for SJS/TEN [77]. Furthermore, elevated serum FasL could
be used as a factor for the differentiation between drug al-
lergy and viral exanthem [78]. Similar results were obtained
in another study, where granulysin and sFasL were found to
be elevated in the initial phase of SJS/TEN with a
 156

Table 3 The APACHE II severity of disease classification system

Physiologic variable High abnormal range Low abnormal range

+4 +3 +2 +1 0 +1 +2 +3 +4

Temperature—rectal (°C) ≥ 41° 39–40.9° 38.5–38.9° 36–38.4° 34–35.9° 32–33.9° 30–31.9° ≤ 29.9°
Mean arterial pressure—mm Hg ≥ 160 130–159 110–129 70–109 50–69 ≤ 49
Heart rate (ventricular response) ≥ 180 140–179 110–139 70–109 55–69 40–54 ≤ 39
Respiration rate—(non-ventilated or ventilated) ≥ 50 35–49 25–34 12–24 10–11 6–9 ≤5
Oxygenation: A-aDO2 or PaO2 (mm Hg)
a. FiO2 ≥ 0.5 record A-aDO2 ≥ 500 350–499 200–349 < 200
b. FiO2 < 0.5 record only PaO2 PO2 > 70 PO2 61–70 PO2 55–60 PO2 <55
Arterial pH (preferred) ≥ 7.7 7.6–7.69 7.5–7.59 7.33–7.49 7.25–7.32 7.15–7.24 < 7.15
Serum HCO3 (venous mMol/L) (Not preferred, use if no ABGs) ≥ 52 41–51.9 32–40.9 22–31.9 18–21.9 15–17.9 < 15
Serum sodium (mMol/L) ≥ 180 160–179 155–159 150–154 130–149 120–129 111–119 ≤ 110
Serum potassium (mMol/L) ≥7 6.0–6.9 5.5–5.9 3.5–5.4 3.0–3.4 2.5–2.9 < 2.5
Serum creatinine (mg/100ml) (Double point score for acute renal failure) ≥ 3.5 2.0–3.4 1.5–1.9 0.6–1.4 < 0.6
Hematocrit (%) ≥ 60 50–59.9 46–49.9 30–45.9 20–29.9 < 20
White blood count (total/mm3) (in 1000s) ≥ 40 20–39.9 15–19.9 3–14.9 1–2.9 <1
Glasgow coma score (GCS): (score = 15 minus actual GCS)
[A] Total acute physiology score (APS) sum of the 12 individual variable points
[B] Age points ≤ 44 years = 0; 45–54 years = 2; 55–64 years = 3; 65–74 years = 5; ≥ 75 years = 6
[C] Chronic health points If the patient has a history of severe organ system insufficiency or is immuno-compromised assign points as follows:
a. For nonoperative or emergency postoperative patients—5 points, or
b. For elective postoperative patients—2 points
Definitions
Organ insufficiency or immuno-compromised state must have been evident prior to this hospital admission and conform
to the following criteria:
Liver: biopsy proven cirrhosis and documented portal hypertension; episodes of past upper GI bleeding attributed to
portal hypertension, or prior episodes of hepatic failure / encephalopathy / coma.
Cardiovascular: New York Heart Association Class IV
Respiratory: chronic restrictive, obstructive, or vascular disease resulting in severe exercise restriction, i.e., unable to
climb stairs or perform household duties; or documented chronic hypoxia, hypercapnia, secondary polycythemia,
severe pulmonary hypertension (> 40 mmHg), or respirator dependency.
Renal: receiving chronic dialysis
Immuno-compromised: the patient has received therapy that suppresses resistance to infection, e.g.,
immuno-suppression, chemotherapy, radiation, long term or recent high dose steroids, or has a disease that is
sufficiently advanced to suppress resistance to infection, e.g., leukemia, lymphoma, AIDS
Total APACHE II score Sum of [A] APS, [B] age points and [C] chronic health points

Adapted from Wong DT, Knaus WA. Predicting outcome in critical care: The current status of the APACHE prognostic scoring system. Can J Anaesth 1991; 38(3): 374–83
Clinic Rev Allerg Immunol (2018) 54:147–176
Clinic Rev Allerg Immunol (2018) 54:147–176 157

Table 4 Algorithm for assessment of drug causality in epidermal necrolysis (ALDEN)

Criterion Values Rules to apply

Delay from initial drug Suggestive +3 From 5 to 28 days −3 to 3

component intake to
onset of reaction
(index day)
Drug present in the body
on index day
Prechallenge/rechallenge
Dechallenge
Type of drug (notoriety)
Other cause
Final score − 12 to 10
Compatible +2 From 29 to 56 days
Likely +1 From 1 to 4 days
Unlikely −1 > 56 days
Excluded −3 Drug started on or after the index day
In case of previous reaction to the same drug, only changes for:
Suggestive: +3: from 1 to 4 days
Likely: +1: from 5 to 56 days
Definite 0 Drug continued up to index day or stopped at a time point less than five times −3 to 0
the elimination half-lifea before the index day
Doubtful −1 Drug stopped at a time point prior to the index day by more than five times the
elimination half-lifea but liver or kidney function alterations or suspected drug
interactionsb are present
Excluded −3 Drug stopped at a time point prior to the index day by more than five times the
elimination half-lifea, without liver or kidney function alterations or suspected
drug interactionsb
Positive specific for disease SJS/TEN after use of same drug −2 to 4
and drug: 4
Positive specific for disease SJS/TEN after use of similiarc drug or other reaction with same drug
or drug: 2
Positive unspecific: 1 Other reaction after use of similarc drug
Not done/unknown: 0 No known previous exposure to this drug
Negative - 2 Exposure to this drug without any reaction (before or after reaction)
Neutral 0 Drug stopped (or unknown) −2 or 0
Negative - 2 Drug continued without harm
Strongly associated 3 Drug of the “high-risk” list according to previous case-control studiesd −1 to 3
Associated 2 Drug with definite but lower risk according to previous case-control studiesd
Suspected 1 Several previous reports, ambiguous epidemiology results
(drug “under surveillance”)
Unknown 0 All other drugs including newly released ones
Not suspected −1 No evidence of association from previous epidemiology studyd with
sufficient number of exposed controlsc
Intermediate score = total of all previous criteria −11 to 10
Possible −1 Rank all drugs from highest to lowest intermediate score −1
If at least one has an intermediate score > 3, subtract 1 point from the
score of each of the other drugs taken by the patient
(another cause is more likely)

<0, Very unlikely; 0–1, unlikely; 2–3, possible; 4–5, probable; ≥6, very probable
ATC, anatomical therapeutic chemical; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis
a
Drug (or active metabolite) elimination half-life from serum and/or tissues, taking into into account kidney function for drugs predominantly cleared by
kidney and liver function for those with high hepatic clearance. b Suspected interaction was considered when more than five drugs were present in a
patient’s body at the same time. c Similar drug = same ATC code up to the fourth level (chemical subgroups). d Definitions for “high risk,”“lower risk,”
and “no evidence of association” in Methods
Adapted from Sassolas B et al. ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis:
comparison with case-control analysis. Clinical pharmacology and therapeutics 2010; 88(1): 60–68

consecutive drop during disease progression. This is in con-
trast to sTRAIL, interferon (IFN)-γ, and TNF-α serum con-
centrations, which were stably elevated for a longer time
during the disease course [79].
TARC (serum thymus and activation regulated chemo-
kine), a Th2 chemokine, is not only found to be significantly
elevated in SJS/TEN and other drug allergy reactions, but a
correlation of TARC serum levels and drug-associated periph-
eral eosinophil count was identified. Therefore, the group of
Quaglino discusses the possibility that not only Th1 but also
Th2 cells might be implicated in SJS/TEN [80] as seen in
other drug allergy reactions, such as DIHS (drug-induced
158
hypersensitivity syndrome) and maculopapular exanthems
[81].
In a recent study analyzing data of 155 patients
(RegiSCAR and Taiwan with SJS/TEN), serum IL-15 and
granulysin levels could be linked to disease severity. In addi-
tion, for patients with elevated serum IL-15 levels a higher
number of fatalities was shown [82].
In SJS/TEN patients, elevated serum microRNA-124
levels were detected by real-time PCR that showed a good
correlation with SCORTEN and the extent of skin involve-
ment [83].
Drug Testing
To identify the culprit drugs, in vitro drug tests, patch
testing, and in certain cases human leukocyte antigen
(HLA)- or non-HLA-associated gene variant testing are
used. Due to the severity of the disease, intradermal
tests and systemic re-exposure, being the gold-standard
procedures in allergy workup settings, must be strictly
avoided in SJS/TEN. Therefore, patch testing may be
considered the only test that re-exposes the patient to
the culprit drug.
Patch tests show an acceptable sensitivity, yielding pos-
itive results in 50% of patients with AGEP [84] as well as
in 50% of patients with maculopapular exanthem [85]. In
a larger France-based multi-center study, these findings
could be confirmed, the culprit drug being identified in
64% of patients with DRESS and 58% of patients with
AGEP [86]. Also, in an India-based single-centre study in
61% of patients with DRESS the culprit drug could be
identified by patch-testing [87]. In contrast, the sensitivity
of patch-testing is disappointing in SJS/TEN, though no
relevant adverse side effect was seen. In the above men-
tioned studies the culprit drug could be identified by patch
testing in 10% [84], 0% [85], 24% [86], and 0% [87],
respectively, in SJS/TEN patients. Only for carbamazepine
the sensitivity of patch testing seemed to be better in a
single-center study, where 10 of 16 patients, thereof 13/16
with HLA-B*1502 allele, were tested positive. Epidermal
re-exposure to carbamazepine was not associated with rel-
evant systemic side effects in this study. Cross-reactivity to
carbamazepine E, CBZ-10,11 epoxide, oxcarbazepine, phe-
nytoin, and in two patients also to lamotrigine, was dem-
onstrated in several cases. It could be shown that sensiti-
zation to different aromatic anti-epileptics plays a role not
only in DRESS, but also in SJS/TEN. As a consequence,
aromatic anti-epileptics should be avoided in these cases
[88].
However, caution is advised in HIV infected individuals
treated with anti-tuberculous medications known to induce
SJS/TEN. Lehloenya et al. reported on two systemic reactions
Clinic Rev Allerg Immunol (2018) 54:147–176
during patch testing. One patient epicutaneously re-exposed to
isoniazid presented with fever, eosinophilia, elevated trans-
aminases, and a morbilliform rash within 24 h. The other
patient exposed to pyrazinamide showed a more severe
reaction with fever, edema, epidermal necrosis of less than
10%, and mucositis [89]. Fortunately, in both cases, the
reaction was not fatal.
Lymphocyte Transformation Test (LTT)
Due to the limited validity of patch testing in SJS/TEN and the
contraindication for other tests linked to re-exposure, in vitro
tests have to be developed and used for the identification of
the culprit drugs. The most frequently used in vitro test in
delayed drug hypersensitivity reactions is the so-called lym-
phocyte transformation test (LTT), synonymic to lymphocyte
proliferation test, or lymphocyte stimulation/activation test.
By using this assay, lymphocyte proliferation as indicator of
drug-specific T cell reactivity is analyzed after stimulation
with a drug, classically by measuring incorporation of radio-
active thymidine into DNA of proliferating cells. Whereas the
LTT shows a sensitivity of 50% or higher in generalized
maculopapular and bullous exanthem, AGEP, DRESS, and
generalized most severe forms of anaphylaxis, the validity in
TEN is low (< 10%) [90]. However, LTT performed in pa-
tients with anti-convulsive drug-related delayed hypersensi-
tivity to carbamazepine, phenytoin, phenobarbital as well as
lamotrigine showed positive results in 50% of cases in a
single-center study [91]. In contrast, in another study LTT
was only positive in 1/9 patients with lamotrigine-induced
SJS/TEN in the acute phase, and in 3/14 patients during the
healing phase [92]. Kano et al. described a decrease of prolif-
eration in two SJS patients during the course of disease,
pointing to the importance of the right timing of LTT in the
early phase of SJS/TEN [93]. Similar results were obtained in
another study, where serial LTTs were performed 10.5 months
apart, showing a reduction of proliferation over time [94]. In
order to improve sensitivity of LTT, in a modified assay T
regs/CD25high cells were removed before incubation of the
remaining lymphocytes with drugs. In a study on patients with
well-documented drug hypersensitivity reactions, an increase
in specificity from 25 to 82% and a significant increase of
drug-specific lymphocyte proliferation by this measure could
be obtained [94]. However, performing LTT after depletion of
T regs in the acute and recovery phase of lamotrigine-induced
SJS/TEN did not show a significant increase of sensitivity or
proliferation rate [92].
An alternative and faster approach of measuring T cell pro-
liferation is the analysis of CD69 upregulation by FACS. Test
results are usually available within 48 h compared to 7 days
with LTT. So far, only two patients previously identified by
LTT were analyzed using this method [95]. The poor
Clinic Rev Allerg Immunol (2018) 54:147–176
sensitivity of conventional LTT in TEN led to the develop-
ment of further alternative tests such as conventional IFN-γ
ELISPOT. A third means to improve LTT consisted of lym-
phocyte pre-treatment with CD3/CD28 antibody and IL-2 for
7 days, and T cell response was tested with modified IFN-γ
ELISPOT. In a small study analyzing SJS/TEN patients, pre-
treatment led to a higher sensitivity compared to the LTT with
non-pre-treated lymphocytes. However, the small number of
patients analyzed does not allow definitive conclusions [96].
An interesting approach is the evaluation of anti-PD-L1
(programmed death-ligand 1) antibody, a checkpoint inhibitor,
in an IFN-γ ELISPOT assay. Analyzing peripheral lympho-
cytes of patients with severe allopurinol-induced drug reac-
tions in conjunction with the active allopurinol metabolite
oxypurinol and allopurinol itself, the authors concluded that
for SJS/TEN and DRESS the sensitivity was higher in the
acute compared to the recovery phase. Furthermore, by adding
anti-PD-L1, an increased test sensitivity in the acute phase
was shown. Thereby, the fact that the lymphocytes of patients
on systemic steroid treatment also showed a higher response
rate when adding PD-L1 antibody compared to the control
group is of particular interest [97].
A new approach to identify a culprit drug in SJS/TEN was
the introduction of a cytotoxicity test that measured granzyme
B and IFN-γ release by ELISPOT, as well as the upregulation
of granulysin on peripheral blood lymphocytes by FACS. In
this context, the effect of IL-7/IL-15 pre-incubation in terms of
positive test results was also evaluated. Although specific cy-
totoxicity assays had a higher sensitivity compared to conven-
tional LTT, the authors concluded that, while maintaining a
high specificity, the sensitivity could only be increased by
combining all three tests. In this test system, pre-incubation
with IL-7/IL-15 was not shown to have a relevant effect [98].
All of the publications showed a limited sensitivity of in
vitro-based assays to identify the culprit drugs in SJS/TEN
patients. Therefore, better drug assays have to be searched for.
Drugs Implicated in SJS/TEN
The most frequent single cause of SJS/TEN is drugs. The
median intake time of drugs before symptoms occur is
4 weeks, the most vulnerable time being 8 weeks after the
start of drug intake. However, for low-risk drugs or drugs
not typically implicated in SJS/TEN, there was a latency of
as long as 30 weeks [99]. In general, the risk of SJS/TEN was
not higher for high-risk drugs after 8 weeks than for low risk
drugs. In a case control study using data of patients from
France, Germany, Italy and Portugal, a highly significant cor-
relation between SJS/TEN and antibacterial sulfonamides,
anti-epileptic drugs, nonsteroidal anti-inflammatory drugs
(NSAIDs) of the oxicam type, allopurinol, chlormezanone,
and corticosteroids was established. The authors calculated
159
the risk of these drugs to be as high as five cases per million
users per week [100]. In a follow-up multinational case-
control study (EuroSCAR) involving patients from six coun-
tries (Austria, France, Germany, Israel, Italy, the Netherlands)
from 1997 to 2001, a risk assessment for drugs being used for
a longer time and more recently marketed drugs was carried
out. Thereby, a high risk was confirmed for cotrimoxazole as
well as other antibiotic sulfonamides, allopurinol, carbamaze-
pine, phenytoin, phenobarbital, and oxicam-NSAID. Among
the newer drugs, nevirapine, lamotrigine, sertraline, and pos-
sibly pantoprazole were frequent inducers of SJS/TEN. Due to
multiple confounding factors the interpretation of the risk as-
sociated with drugs such as paracetamol, pyrazolones, acetyl
salicylic acid, tramadol, nimesulide, ibuprofen, corticosteroids
in general as well as dexamethasone and prednisone (predni-
sone, prednisolone, and methylprednisolone) was difficult. A
lower risk to induce SJS/TEN was attributed to acetic acid
NSAIDs, macrolides, quinolones, cephalosporins, tetracy-
clines, and aminopenicillins. Furthermore, for non-antibiotic
sulfonamides (thiazide diuretics, furosemide, and sulfonylurea
antidiabetics), beta-blockers, ACE inhibitors, calcium channel
blockers, propionic acid NSAIDs, insulin, non-pantoprazole
proton pump inhibitors, fluoxetine, non-sertraline serotonin
reuptake inhibitors, and statins, no increased risk was found
[99]. Interestingly, in this study allopurinol was the most fre-
quent inducer of SJS/TEN in the European countries analyzed
as well as in Israel. In this context, several non-HLA-
dependent factors that increase the risk for allopurinol-
associated SJS/TEN were identified. Like for other drugs,
the risk is highest during the first 8 weeks of intake.
However, in contrast to other drugs, there is a clear dose-
dependent increase of the risk in patients taking 200 mg or
more per day [101]. Allopurinol was also shown to be the
most frequent inducer of SJS/TEN in a Canadian population
where triggers could be identified in 75% of patients [102].
However, another Israel-based retrospective study identified
phenytoin as the leading medication to induce SJS/TEN, allo-
purinol being a less frequent inducer in the collective investi-
gated. The authors presumed that the discrepancy between
their results and the results by Halevy et al. might be due to
limitations such as missing controls, unknown drug exposure,
over-the-counter medications as well as a lack of further data
[103]. In a retrospective cross-sectional study at the Kenyatta
National Hospital, SMX/TMP followed by nevirapine were
identified as the two leading drugs inducing SJS/TEN [21].
A systematic review of SJS/TEN in the Indian population
identified antimicrobial drugs (37.27%) as the leading cause
followed by anti-epileptic drugs (35.73%) and NSAIDs
(15.93%). However, regional differences were observed be-
tween South, West, and North India. Anti-epileptic drugs were
the main causative drugs in the Northern Indian population,
whereas in South and West India, the most frequent eliciting
drugs were antimicrobials. Overall, fluoroquinolones were the
160
most frequent antimicrobials involved; however, in West and
North India sulfonamide antibiotics were the most frequent
anti-infectives inducing SJS/TEN. Among the anti-epileptic
medications the aromatic anti-convulsives carbamazepine
and phenytoin were the leading cause for antiepileptic-
associated SJS/TEN. NSAIDs being the third most important
drug group inducing SJS/TEN in India, paracetamol was the
most relevant medication. In contrast to the European study,
antitubercular drugs (5.65%) and anti-malarials (1.28%) could
be linked to SJS/TEN [104]. An analysis of eliciting drugs and
other risk factors in children-based pooled data of the
RegiSCAR and EuroSCAR case-control study showed no
link of herpes infection with SJS/TEN. However, multiple
drug use before onset of SJS/TEN could be identified as a
relevant risk factor. The most frequent drugs inducing SJS/
TEN in children were anti-infective sulfonamides, phenobar-
bital, carbamazepine, and lamotrigine [105]. Atopy however,
could not be linked to an increased risk for SJS associated with
anti-epileptic drugs [106].
Besides conventional drugs, herbal remedies should be
considered as causative agents in patients with TEN. In a
single-centre prospective Indian study, 34% of SJS/TEN were
suspected of being induced by herbal medication [107].
Recently, checkpoint inhibitors including CTLA-4 antago-
nists were described as causative drugs in patients with
TEN. The mechanism of action of these antibodies is de-
creased apoptosis in activated T cells and antagonizing of
inhibitory signals resulting in a higher anti-tumor activity.
Nivolumab (programmed cell death receptor 1; PD-1 anti-
body) alone or in combination with ipilimumab may induce
TEN [108] or TEN-like [109] reactions with severe satellite
cell necrosis. Cetuximab, a chimeric epidermal growth factor
receptor antagonist used in head/neck and colon cancer, was
also found to induce SJS/TEN in patients with or without
concomitant radiotherapy [110–112]. Small molecules like
the BRAF-V600E inhibitor vemurafenib used in metastatic
melanoma were also reported to induce TEN. LTT with
vemurafenib, a molecule that contains a sulfonamide moiety,
showed cross-reactivity with dabrafenib and sulfamethoxa-
zole. Based on these data, a high degree of cross-reactivity
with other drugs containing this sulfonamide group has to be
considered [113]. The observation that dabrafenib was toler-
ated in a patient with vemurafenib-induced TEN suggests that
other moieties than the sulfonamide group within the BRAF-
V600E inhibitor molecule might play a role [114].
Genetics
This section will mainly focus on genetics linked to SJS/TEN,
although there is increasing evidence that similar genetics
might be associated with different adverse drug reactions.
Clinic Rev Allerg Immunol (2018) 54:147–176
Carbamazepine (CBZ), an aromatic antiepileptic, is one of
the first drugs that could be linked to a HLA in SJS. A strong
relationship between HLA-B*1502 and CBZ-induced SJS
was demonstrated in Han Chinese. Chung could show that
all 44 SJS patients investigated (100%) were carriers of this
allele, whereas CBZ-tolerant patients had a lower allele fre-
quency (3%) compared to the general population (8.6%)
[115]. A HLA-B*1502 allele frequency study including nine
different Chinese ethnicities was performed in Yunnan prov-
ince. The HLA-B*1502 allele frequency showed a large dif-
ference between the different ethnic groups ranging from
15.36 (Zhuang) to 4.25 % (Yi). In order to gain a better over-
view of HLA-B*1502-associated CBZ-linked SJS, the au-
thors suggested to study more Chinese ethnic groups [116].
A Malaysian multi-ethnic study showed a significant, though
different association of HLA-B*1502 and CBZ-induced SJS/
TEN in all three populations studied (Malay: 49 (OR),
Chinese: 14.3 (OR), Indian: 13.8 (OR)) [117]. In a Thai
population-based study, all CBZ-induced SJS cases could be
linked to HLA-B*1502, whereas the CBZ-tolerant group had
a HLA-B*1502 allele frequency of 18% [118]. Also, an asso-
ciation of the HLA-*1502 allele with CBZ-induced SJS in six
of eight Indian patients was found by Metha et al., suggesting
an association of the incriminated drug with the studied allele
as well [119].
However, these findings could not be confirmed in all
Asian populations. Thus, CBZ-induced SJS/TEN was not
found to be linked to HLA-B*1502 neither in Koreans that
have a low HLA-B*1502 allele frequency nor in a Japanese
study [120–122].
In three European studies, no correlation was found be-
tween HLA-B*1502 and CBZ-induced SJS/TEN in
Caucasian patients [123–125], probably due to the low allele
frequency of 0.06% in this population [125].
Due to the high allele frequency found not only in Han
Chinese but also in other Asian ethnics, the US FDA recom-
mends HLA-B*1502 genotyping in all Asian patients before
administering CBZ [126]. In the Sri Lankese population, the
overall allele frequency of HLA-B*1502 was 4.3%, with the
highest frequency being found in the Singhalese (9.3%). The
authors concluded that larger studies are necessary to validate
these results, especially in terms of the US FDA screening
recommendations [127].
A statistically significant association of HLA-B*1502 with
other antiepileptic drugs causing SJS/TEN could also be
shown in Han Chinese. HLA-B*1502 was related to
oxcarbazepine in 100% of SJS cases, phenytoin in 30.8%,
and lamotrigine in 33%, respectively. Based on these data,
the authors concluded that patients with HLA-B*1502 should
not be exposed to any aromatic anticonvulsive drugs due to
the similar structure of these molecules. According to Hung
et al., lamotrigine should only be used carefully in these pa-
tients [128]. A relevant association of HLA-B*1502 with
Clinic Rev Allerg Immunol (2018) 54:147–176
phenytoin-induced SJS was also found in the Thai population.
In the study by Locharernkul et al., all SJS patients were HLA-
B*1502 carriers compared to 18% of the phenytoin-tolerant
patients [118]. Similar findings were shown in a publication
including patients from Taiwan and Thailand where HLA-
B*1502, but not HLA-A*3101, was highly related to
oxcarbazepine-induced SJS [129]. Phenytoin-induced SJS/
TEN in Malaysia was not only found to be associated with
HLA-B*1502 but also with HLA-B*1513. However, HLA-
B*1513 could also be genetically linked to phenytoin-induced
DRESS [130]. The association of HLA-B*1502 with
phenytoin-induced SJS in Han Chinese and Malaysians
discussed above was not observed in a Thai study population.
However, here an association in terms of the CYP2C9*3 poly-
morphism could be established with phenytoin-related SJS/
TEN, but not with phenytoin-related DRESS [131].
In a Southern Han Chinese population, HLA-A*2402 was
identified as an independent risk factor for SJS/TEN induced
by aromatic antiepileptics. The relevant association of HLA-
A*2402 was not only seen with aromatic antiepileptic drugs
as a whole but also for each individual drug tested (CBZ,
phenytoin, lamotrigine). Furthermore, an association of
HLA-A*2402 with several HLA-B*1502 negative CBZ-
related SJS/TEN cases was documented [132].
Khor et al. found CBZ-SJS/TEN patients with a significant
correlation to HLA-B*1502 as well as to HLA-A*3101 in the
Indian population of Malaysia. Therefore, it was suggested to
perform genetic testing for both alleles before prescribing
CBZ [117].
CBZ-SJS/TEN in Japan does not seem to be linked to
HLA-B*1502, but in a small study, HLA-B*1511 could be
documented in four of 12 patients [121]. Recently, a Spanish
population-based study identified a significant correlation of
HLA-A*1101 with CBZ-associated SJS/TEN with the limita-
tion of the small number of cases analyzed [125].
Allopurinol as a major cause of SJS/TEN was studied ex-
tensively in terms of genetic linkage. In a Taiwanese study, 51
patients that developed SJS/TEN (SJS: n = 13, SJS/TEN over-
lap: n = 5, TEN: n = 3) or DRESS (n = 30) to allopurinol were
investigated. Both patient groups showed a strong correlation
with HLA-B*5801, whereas only 15% of HLA-B*5801 car-
riers were documented in the allopurinol tolerant group [133].
In a Thai population-based study on allopurinol-induced SJS/
TEN, but not allopurinol-induced DRESS, a 100% (27 out of
27 patients) correlation of allopurinol-SJS/TEN with HLA-
B*5801 was shown as was also seen in the Taiwanese popu-
lation [134]. A relevant association of HLA-B*5801 and
allopurinol-associated SJS/TEN could also be found in
Japan [122, 135] and South Korea. In the South Korean study
by Park et al., eight of nine patients were positive for HLA-
B*5801, the allele frequency in the tested population being
7%. Based on these findings, the authors assumed that genetic
testing before the use of allopurinol might be cost-effective
161
[120]. In the European-based RegiSCAR, 27 of 31 patients
with allopurinol-related SJS/TEN were of European ancestry.
Fifteen of these 27 patients (55%) were positive for HLA-
B*5801 compared to 28/1882 individual controls (1.5%),
the calculated OR being 80. In the Caucasian population, there
is a significant association of HLA-B*5801 with allopurinol-
SJS/TEN [123], though to a lower extent compared to the Han
Chinese [133] or Thai populations [134].
The growing evidence for the fact that HLA-dependent
and HLA-independent genetic factors play a significant,
though not the only role, in inducing severe adverse drug
reactions, raises the question whether genetic screening be-
fore use of the drug is cost-effective or not. A Taiwanese
cost-effectiveness study based on data of the Taiwan NHI
program concluded that screening for HLA-B*5801 does
not only prevent severe allopurinol-induced drug reactions
but also shows a cost benefit in terms of prescribing the
most suitable urate-lowering drug [136]. In a US-based
cost-effectiveness study analyzing allopurinol prescription
with/without previous genetic testing, a potential benefit of
genetic testing was seen in Asians and Afro-Americans, but
not in other ethnic groups [137].
In the context of SJS/TEN related to locally applied drugs,
the carboanhydrase inhibitor methazolamide is of specific in-
terest. Yang et al. were able to show that HLA-B*5901 is
strongly linked to methazolamide-associated SJS/TEN not on-
ly in Han Chinese but also in Koreans [138, 139].
Regarding adverse drug reactions to SMX/TMP in Thai
patients, a particular interest is drawn to the HLA-B*1502-
C*0801 haplotype as this constellation is associated with a
14-times higher risk of developing SJS/TEN [140].
HLA-A*0206 is known to be strongly associated with cold
medicine-associated SJS/TEN with severe ocular complica-
tions. Using a whole-genome sequencing approach on an
ethnicity-specific array of 1070 unrelated Japanese persons,
new genetic polymorphisms were identified. Therefore, these
polymorphisms, TLR3 and PTGER3, must be interpreted as a
complementary factor in the presence of HLA-A*0206 [141].
Nevirapine-induced SJS/TEN cases from Mozambique
were recently linked to two different non-HLA-associated
gene variants. A gene variant of TRAF3IP2 (implicated in
immune response and NFkappa activation) and the null-
genotype of GSTM1 (glutathione-S-transferase), leading to a
delayed metabolization, are both independently related to a
higher incidence of nevirapine-SJS/TEN [142].
Pathophysiology of SJS/TEN
In the past years, understanding of the pathogenesis of SJS/
TEN has improved considerably. In this context, drug-specific
cytotoxicity mediated by T cells, genetic linkage with HLA-
and non-HLA genes, TCR restriction, and cytotoxicity
162
mechanisms were clarified. However, many factors contrib-
uting to epidermal necrolysis still have to be identified, espe-
cially in virus-induced and autoimmune forms of epidermal
necrolysis not related to drugs. In early blister fluid of SJS/
TEN patients, cytotoxic CD8+ T cells and NK-like cytotoxic
T cells are the most important cells, whereas in later phases
monocytes become predominant [143]. This is in contrast to
the dermoepidermal zone, where CD14+ monocytes are
found in relevant concentrations. The presence of these rele-
vant CD14+ monocytes expressing CD80, CD86, and
CD137 in pre-blister stages might contribute to enhanced
CD8+ T cell cytotoxicity and proliferation [144]. The specif-
ic role of elevated soluble IL-2 receptor levels found in blis-
ters remains speculative [145]. Furthermore, Nassif et al.
showed that CD8+ T cells found in blisters were SMX/
TMP- or CBZ-specific and granzyme B positive. Therefore,
it was suggested that cytotoxicity was probably related to
granzyme B. Due to a missing inhibition using anti-Fas anti-
bodies, drug-specific T cell-mediated killing was thought to
be most likely perforin/granzyme-associated [146].
Interestingly, in two patients, significant amounts of CD4+
T cells were found in the blisters. According to Teraki et al. a
participatory role of pro-inflammatory mechanisms might be
attributed to IL-17+CD4+ T cells which are found in blisters
and peripheral blood in equal amounts during the early phase
of disease [147]. Still, the role of FasL in keratinocyte apo-
ptosis remains controversial. Abe et al. not only found high
amounts of soluble FasL in sera of SJS/TEN patients but
were also able to detect FasL expression upon drug-specific
lymphocyte activation. As in short cultured Fas-positive
keratinocytes apoptosis could be induced by soluble FasL,
this was suggested to be a relevant mechanism in SJS/TEN
[148]. An indirect FasL-mediated killing mechanism was
suggested by Viard-Leveugle et al. who showed that activat-
ed T cells produce TNF-α and IFN-γ with a consecutive
increase of iNOS and a relevant upregulation of FasL-
positive keratinocytes leading to FasL/Fas and Caspase-8-
induced apoptosis [149]. As IFN-γ activated keratinocytes
were shown to express FasL, TNF-α, and IL-10, Nassif et al.
state that these mediators more likely play a role in downreg-
ulation of cytotoxic lymphocytes than in autocrine/paracrine
FasL/Fas-mediated keratinocyte apoptosis, as was suggested
by Viard et al. [150].
FasL, TNF-α, perforin, and granzyme B were detected
by PCR in blister fluid and peripheral blood lymphocytes in
different delayed-type hypersensitivity reactions, but the
highest levels were found in SJS/TEN [151]. Perforin-
positive lymphocytes may be detected in blisters, but also
in the dermal parts of skin lesions with epidermal damage in
SJS patients [152]. CD8+ T cell-mediated cytotoxicity to
sulfamethoxazole and metabolites was shown to be HLA-
I-specific and was not altered by blocking the FasL/Fas or
TNF-related apoptosis-inducing ligand (TRAIL)/TRAIL-R
Clinic Rev Allerg Immunol (2018) 54:147–176
pathway [153]. Another enlarged concept suggests that be-
sides CD8+/HLA-I-restricted killing, CD1+ and CD14+
cells might add to keratinocyte damage in SJS/TEN, due
to the production of TRAIL and TNF-like weak inducer of
apoptosis (TWEAK). Both TRAIL and TWEAK might con-
tribute synergistically to keratinocyte apoptosis, together
with IFN-γ and TNF-α found in high concentration in blis-
ter fluids [154].
HLA-E-specific activating receptor CD94/NKG2C is
found on activated cytotoxic T cells and natural killer (NK)
cells that degranulate when stimulated by HLA-E-positive
cells [155]. However, there is increasing evidence that soluble
15 kDa granulysin, present in cytolytic granules of cytotoxic T
lymphocytes and NK cells, is a key player in epidermal
necrolysis. The key role of granulysin is further supported
by the observation that in T cells and NK cells from blisters,
a high amount of granulysin expression was found. Also,
granulysin is predominantly found in blister fluid. As a con-
sequence, injection of soluble granulysin in mice could be
shown to trigger widespread epidermal necrosis [74].
Schlapbach et al. demonstrated that different levels of
granulysin can be detected in CD8+ and NKp46 cells, not
only in SJS/TEN patients, but also in other forms of cutaneous
drug reactions [156]. Granulysin expression could be detected
upon drug-specific T cell activation. Furthermore, granulysin-
positive cells were found in the upper dermis.
Due to the significant relation of CBZ-induced SJS with
HLA-B*1502 in Asian populations, the focus was put on
the interaction of CBZ with the HLA-complex. In this con-
text, Yang et al. were able to show that there was a non-
covalent binding between the studied drug and the HLA-
complex, suggestive for a mechanism according to the p-i
concept [157]. In contrast to the well-studied abacavir hy-
persensitivity in HLA-B*5701 positive patients, it could be
demonstrated by using drug-pulsing and APC-fixing assays
that no intracellular pathway is mandatory to present CBZ
in the HLA-/MCH cleft [158]. Although there is a high risk
of developing SJS/TEN in patients with an HLA-B*1502
profile taking CBZ, most of the HLA-B*1502-positive pa-
tients tolerate CBZ. This may be explained by the fact that
only patients with a certain TCR profile developed SJS/
TEN. In this context, the VB-11-ISGSY clonotype was
identified in 16 of 19 patients with CBZ-associated SJS/
TEN, whereas this clonotype was not found in HLA-
B*1502-positive CBZ-tolerant patients [159]. T cell activa-
tion demonstrated by granulysin and IFN-γ production
could also be seen in allopurinol-associated SJS/TEN and
–DRESS. Thus, T cell activation was only found upon
stimulation with oxypurinol, the active metabolite of allo-
purinol, but not allopurinol itself or febuxostat.
Interestingly, like in carbamazepine-induced SJS/TEN, a
TCRvβ subtype with consecutive clonal proliferation was
identified here [160].
Clinic Rev Allerg Immunol (2018) 54:147–176
Acute and Chronic Complications of SJS/TEN
In the RegiSCAR study, the fatality rate of SJS/TEN was 23%
at 6 weeks with a strict correlation to the severity of the disease
(SJS, SJS/TEN, TEN), and 34% at one year with a direct
correlation to comorbidities, but not to the disease severity
[161]. A post-hospital discharge survey from a Chicago-
based study reported an estimated 5-year survival rate of
65%, compared to the RegiSCAR study. In this study, the
surviving patients had a high prevalence of ocular, skin, and
renal sequelae. Multivariate analysis showed that a
SCORTEN of 3–6 and delayed referral to burn units of 5 days
or more were predictors of late fatality [162]. In acute SJS/
TEN multi-organ involvement is a typical feature. Apart from
mucocutaneous involvement in almost 100%, most patients
have multi-organ involvement with varying degrees of sever-
ity [64, 163]. In acute SJS/TEN, septicemia is a leading cause
of morbidity and fatality [164]. In a recent single-center study,
bacterial infection rate was 91.7%, and septicemia rate was
62.5% with a relatively low fatality rate of 12.5%. The authors
speculated that the lower fatality rate observed in their cohort
was due to a lower SCORTEN and to more specified care as
compared to other studies [164]. In the study by McGee et al.,
analyzing patients referred to a specialized burn center, pa-
tients with positive bacterial blood cultures on admission
had a 100% fatality rate, in contrast to a mortality rate of 7%
in patients with negative bacterial blood cultures before refer-
ral [165]. The probability of positive blood cultures was cor-
related with delayed admission to the specialized burn centre
of 7 or more days. Furthermore, Hermiz et al. analyzed the
effect of hospital-acquired infections on mortality in SJS/TEN
patients. They observed an increase in fatality from 20.9 to
66% in case of infection [166]. The most common pathogens
isolated in this study were MRSA and Pseudomonas
aeruginosa, and to a lesser extent Candida,
Stenotrophomonas and Acinetobacter. Antibiotics were the
leading cause for death in patients with drug-induced SJS/
TEN. These patients were at a higher risk to develop severe
septicemia. The authors of this study concluded that in
antibiotic-associated SJS/TEN secondary resistance of the
bacteria was responsible for the fatal outcome [167]. Similar
findings with a mortality rate of 38%, mostly attributed to
sepsis, were demonstrated in a German study, where antibi-
otics were the second most frequent cause of fatality, after
antimetabolites [168]. Like in the other study, the authors con-
cluded that antibiotic resistance led to bacterial sepsis and
subsequent fatality.
With a prevalence of 42.9%, pneumonia is a major com-
plication of SJS/TEN with almost half of the patients requiring
mechanical ventilation. Cultures from bronchial secretions re-
vealed MRSA in 33.3%, Candida albicans in 11.1%, and
Gram-negative bacteria in the remaining 55.6% patients
[169]. In a retrospective larger cohort study, 25% of patients
163
had to be mechanically ventilated, half of which died [170].
TEN-associated respiratory symptoms with hypoxemia but
normal chest X-ray were seen in 27%, which might be indic-
ative for pulmonary/bronchial involvement in early stages of
TEN. Lebargy et al. reported that mechanical ventilation was
required in the majority of these patients and was associated
with a poor prognosis [171]. Mild pulmonary dysfunction is
seen in about half of all SJS/TEN patients as a long-term
complication [172]. Since pulmonary involvement is connect-
ed to the severity of ear, nose and throat (ENT) symptoms in
severe cases, a complete ENT workup is necessary, not only to
diagnose the severity of nasopharyngeal mucosal involvement
but also to evaluate a possible pulmonary involvement. Within
1 year after SJS/TEN, almost all patients showed complete
healing of the oropharyngeal mucosa [173]. A rare pulmonary
complication of SJS/TEN is bronchiolitis obliterans. In case of
progressive respiratory failure, physicians should be aware of
this chronic, potentially fatal complication [174].
In patients with dysphagia, esophageal implication should
be considered as was reported by Lamireau analyzing five chil-
dren with esophageal mucosal blistering and ulcerations [175].
Single case reports exist on diffuse [176] and necrotic esopha-
geal manifestations [177] in acute SJS/TEN as well as on sec-
ondary esophageal strictures [178, 179] as a late complication
of SJS/TEN. A gastro-intestinal diagnostic workup should al-
ways be considered as also small bowel/colon involvement and
perforated diverticulitis were reported in TEN. In both cases,
surgical interventions were needed [180, 181].
A further complication of SJS/TEN regarding mucosal sur-
faces is vulvo-vaginal involvement with a frequency of up to
75% and long-term sequelae in 25% of patients. As acute
manifestations, erosions and ulcerations are seen, whereas
chronic manifestations predominantly consist of strictures
[182, 183].
Renal dysfunction is an acute complication seen in up to
14.9% of all patients with SJS/TEN [163, 184]. In up to 23.2%
of SJS/TEN patients, hematuria is reported [64]. In other stud-
ies, up to 27.9% of all SJS/TEN patients dialysis was needed
[168]. Among other factors, pre-existing chronic kidney dis-
ease and acute sepsis were associated with an increased risk of
developing acute renal failure in SJS/TEN. According to
Hung et al., 5% of the patients analyzed required long-term
dialysis [185]. Dialysis was shown to be an independent ad-
ditional risk factor for mortality in this context [168, 186].
According to Wang et al., hepatitis occurred with a fre-
quency of 36.4% in a series of 58 SJS/TEN patients investi-
gated. Gastrointestinal symptoms (12.5%), encephalopathy
(2.3%), myocarditis (5.7%), and disseminated intravascular
coagulation (8%) were reported much less frequently [163].
Though cholestatic liver disease is only rarely seen in SJS/
TEN [187], the appearance of jaundice in drug-induced liver
injury associated with SJS/TEN was related to an increased
mortality rate of 45.5% [188]. As a complication of, or in
164
association with drug-induced SJS/TEN, secondary acute
vanishing bile duct syndrome (VBDS), where bile duct de-
struction leads to cholestasis, represents a potentially fatal dis-
ease. Patients should be evaluated for VBDS in case of in-
creasing cholestatic parameters. VBDS was linked with dif-
ferent drugs by several authors. Among the reported potential-
ly eliciting drugs ibuprofen [189–191], ciprofloxacin [192],
acetaminophen [193], azithromycin, [194] and carbamazepine
[195] are found. According to the recent publication by White
et al. TNF-alpha blockade and/or plasmapheresis may offer a
treatment option for VBDS [196].
Ocular Complications
Acute ocular complications are seen in the majority of SJS/
TEN patients with a frequency of 40% in SJS and 75% in
TEN. Although less patients with SJS compared to TEN de-
veloped ocular symptoms, there was no statistically signifi-
cant difference regarding the frequency of severe ophthalmo-
logical manifestations (20 vs 33%) [197]. Comparable results
were found in a French study with 74% of all SJS/TEN-
patients analyzed suffering from mostly mild ocular compli-
cations. In accordance with the other report, TEN patients
were more frequently affected compared to SJS patients, but
no difference regarding severe forms was seen. Fifteen months
after acute SJS/TEN, 63% of all patients had late symptoms
with dry eye syndrome being the predominant manifestation
[198]. Sotozono et al. were able to identify previous NSAID/
cold-remedy intake and young age as risk factors for the de-
velopment of acute ocular manifestations [199]. A direct link
of inflammation and ulceration of the tarsal conjunctiva and
lid margin in acute SJS/TEN with corneal complications was
found [200]. Early amniotic membrane transplantation is a
current treatment strategy with the goal of diminishing the risk
of secondary scarring and visual impairment [201]. An ad-
vanced treatment protocol in the case of treatment failure
was described by Tomlins et al. called triple-TEN treatment.
It comprises subconjunctival triamcinolone injection, amniot-
ic membrane tissue application, and insertion of an acrylic
scleral shell spacer in order to reduce the risk of late onset
sequelae [202].
In order to assess the chronic ocular manifestations in SJS/
TEN patients, Sotozono et al. introduced a new grading sys-
tem, including 13 potential complications [203]. Cataract is
one chronic complication of SJS/TEN, and in case of visual
impairment, cataract surgery should be evaluated. Narang
et al. were able to show in 32 operated patients (40 eyes) that
not only the visual acuity significantly improved but also that
the ocular surface condition remained stable in 35 of 40 oper-
ated eyes [204]. A South African study found that 89% of
patients with SJS/TEN had mild long-term ocular complica-
tions. In this analysis no difference between HIV-infected and
Clinic Rev Allerg Immunol (2018) 54:147–176
non-HIV-infected patients was observed [205]. Unfortunately,
systemic therapy neither with IVIG or corticosteroids nor with
a combined IVIG and corticosteroid treatment had a signifi-
cant effect on the final visual outcome and the chronic ocular
surface complication score six months after SJS [206].
Another new grading system as well as a new therapeutic
strategy using topical humanized anti-VEGF monoclonal an-
tibody bevacizumab was introduced by Uy et al. in 2008.
Patients involved in the study demonstrated a decrease in oc-
ular neovascularization and an improvement of visual acuity
[207].
In children, similar results regarding acute and chronic oc-
ular manifestations in SJS/TEN patients were found. A major-
ity of children with SJS/TEN have ocular involvement during
the acute phase, but some develop ocular manifestations only
in the healing time of SJS/TEN, necessitating a thorough oph-
thalmological follow-up [208].
Other Long-Term Complications
In a Taiwan-based study on 102 patients, Yang et al. identified
almost half of the patients having long-term skin and eye
sequelae. Chronic eczema was seen in 31.4% and hypo- and
hyperpigmentation in 13.7% of patients. Long-term nail com-
plications such as anonychia, dystrophic nails, and pterygium
were observed in 11.8% of patients. Autoimmune diseases
(Sjögren or Sjögren-like syndrome, systemic lupus
erythematosus/Hashimoto thyroiditis) were documented in
six and deterioration of chronic kidney disease in two patients,
respectively [209]. In contrast to hypo- and hyperpigmenta-
tion, hypertrophic scars and keloids are only rarely seen fol-
lowing SJS/TEN [210–213].
Acute Management of SJS/TEN
Supportive Care
SJS/TEN is a multi-organ disease [64, 163, 214, 215] that not
only affects the skin and mucous membranes but also several
internal organs. Therefore, a multi-disciplinary approach is
required. In a first step, immediate withdrawal of potentially
causative drugs, ideally in the early stages of the disease, is
mandatory to reduce fatality in SJS/TEN. In addition, it has to
be recognized that drugs with a long half-life seem to be as-
sociated with a higher mortality rate [216]. Nowadays, imme-
diate referral to a specialized unit, such as burn centers, for
optimized supportive care is a priority. Silver-releasing wraps/
dressings are the therapy of choice, although studies compar-
ing silver-releasing non-adhesive wraps to other local treat-
ments are lacking.
Clinic Rev Allerg Immunol (2018) 54:147–176
The use of air-fluidized beds should be considered in SJS/
TEN patients, as faster reepithelialization, a lower rate of com-
plications and, most notably, less cutaneous infections were
found in a single-center study [217].
The importance of a quick referral to burn centers is given
by the fact that increased mortality may be seen in case of
delayed admission of 7 days or more after onset of symptoms
[60]. There is lack of consensus whether debridement should
be undertaken [218]. As to supportive treatments, it was ad-
vised to prefer enteral to parenteral nutrition, as the latter is
associated with an increase in fatality rate [60].
Bacterial infections are a major reason for complications in
a large part of patients. In a recent small Swedish study, in 22
out of 24 patients at least one positive bacterial culture was
detected [164]. In this study, sepsis occurred in 15 patients,
most of which initially had a positive bacterial skin swab.
Patients receiving empirical antibiotic treatment at an early
stage of disease were found to have a lower rate of different
bacterial species identified in the swabs. The authors recom-
mend isolation of the patients and use of barrier methods in
order to reduce the number of systemic infections. Although a
potential effect of empiric antibiotic therapy in the initial
stages of SJS/TEN could be shown, the authors do not gener-
ally recommend antibiotic coverage due to the small number
of patients investigated in this study.
Also, appropriate information and emotional support for
the patients and their families is essential in the acute manage-
ment of SJS/TEN. It is important to keep in mind that patients
who survive SJS/TEN have to cope with psychological com-
plications and decreased health-related quality of life
[219–222].
Corticosteroids
Concerns about the use of glucocorticoids in SJS/TEN pa-
tients were mainly related to the high rate of bacterial
infection/sepsis in SJS/TEN [164, 215] and the slow rate of
reepithelialization of the affected skin. However, early dexa-
methasone pulse therapy in SJS/TEN did not alter the time of
disease stabilization (2.3 days) and of reepithelialization
(13.9 days) [223]. Also, no increase in sepsis incidence was
shown [223, 224]. In case of prior use of glucocorticoids for
treatment of other diseases, the time to stabilization was longer
by 2.2 days. Other parameters such as morbidity and fatality
did not differ in patients with or without prior use of gluco-
corticoids [225].
Due to the rarity and heterogeneity of SJS/TEN, in general,
only retrospective observational open-label single-center stud-
ies are available. In a retrospective observational study in pa-
tients from Germany and France (EuroSCAR study) evaluat-
ing the efficacy of glucocorticoids for the treatment of SJS/
TEN, glucocorticoids were not found to be superior to sup-
portive care only in terms of mortality [226]. A meta-analysis
165
of 11 studies (patient collective of Schneck et al. included)
evaluating the effectiveness of glucocorticoids versus support-
ive care only, showed comparable results between patients on
corticosteroids (n = 367) and patients receiving supportive
care only (n = 396) in general and no increased mortality
was found [227]. However, in other studies, a certain benefit
of corticosteroids could be identified. In the small study by
Araki et al., a significant reduction in ocular complications
was seen, if steroid pulse therapy was initiated early in the
disease [228]. In a Korean study, the use of IV dexamethasone
was associated with lower than expected ocular involvement
[229]. In a six-months’ prospective study conducted in
Calcutta, 14 of 20 TEN patients enrolled received dexameth-
asone injections at a dose of 1 mg/kg per day within 3–7 days
after disease onset. In this study, no mortality was observed.
Therefore, the authors concluded that the early introduction of
systemic corticosteroids was life-saving and should be consid-
ered as a low-cost therapy in countries with a limited health
budget [230].
Immunoglobulins
Based on the finding that human intravenous immunoglobulin
(IVIG) products lead to inhibition of Fas-mediated keratinocyte
apoptosis when applied on keratinocytes in vitro, 10 patients
with TEN were treated with IVIG in a pilot study in the 1990s
[231]. As there was no mortality observed, the authors conclud-
ed that IVIG may be considered an effective treatment of TEN.
In a subsequent retrospective multi-center study including 12
patients with SJS, a high-dose IVIG regimen of 0.6 g/kg/day
over 4 days was given. No fatality at 45 days was observed and
the time to complete healing in patients receiving IVIG early in
the disease was shorter [232]. In a multi-center retrospective
study by the same group on the effectiveness of high-dose
IVIG (2.7 g/kg bodyweight on average) in 48 patients [233],
survival rate was 88% at day 45. Patients receiving IVIG in high
doses in the initial stages of TEN typically showed a better
treatment response. Furthermore, analyzing different IVIG
batches, the authors found a significant difference in the capac-
ity of blocking Fas-mediated keratinocyte apoptosis in vitro.
Trent et al. investigated the effect of high-dose IVIG in 16 adult
patients with an average length of stay in the hospital of
20.31 days based on the SCORTEN-predicted mortality rate
[234]. Though the SCORTEN had predicted 5.18 fatalities, on-
ly one fatality was observed in this retrospective analysis. The
effect of IVIG in SJS, SJS/TEN overlap, and TEN was studied
in a newer retrospective analysis of 64 patients in Singapore
[235], 28 patients fulfilling criteria for SJS/TEN overlap and
36 for TEN. All patients received IVIG, and were divided into
two subgroups of 32 patients with and 32 patients without cor-
ticosteroid treatment prior to IVIG application. Furthermore, the
patients were divided into groups with low (< 3g/kg
bodyweight, n = 42) or high (≥ 3g/kg bodyweight, n = 9)
166
IVIG dose. Irrespective of a low or high IVIG dose applied,
IVIG did not show any benefit in terms of expected mortality. A
meta-analysis including nine studies comparing the effect of
IVIG vs supportive care in terms of mortality did not show a
beneficial effect of IVIG in general. However, the different
IVIG doses used were not considered [227]. Barron et al. per-
formed a SCORTEN-based analysis of 13 studies different from
the prior meta-analysis that included an IVIG treatment group
[65]. The authors conclude that, when excluding two studies
with low-dose IVIG, the sensitivity analysis showed a trend
towards a beneficial effect of IVIG with respect to standardized
mortality rate (SMR). However, heterogeneity of patient collec-
tives, supportive care, and concomitant corticosteroid treatment
rendered conclusions difficult. Huang et al. performed a sys-
tematic review and meta-analysis of 11 studies including nine or
more TEN patients treated with IVIG with regard to SCORTEN
[236]. The SMR was shown to be equal in low- and high-dose
IVIG-treated patients, no statistical clinical effect of IVIG being
observed in either group in terms of SMR.
In contrast, in an Indian prospective open-label study, low-
dose IVIG in combination with steroids showed a benefit in
terms of reduced mortality and recovery time in TEN patients
[237]. Although in a systematic review and meta-analysis no
benefit in patients treated with high-dose IVIG could be seen,
in terms of mortality, the early use of IVIG compared to pa-
tients receiving only supportive care or corticosteroids was
shown to be effective in a single center [238].
In conclusion, the use of IVIG remains controversial, al-
though a positive effect in single patients is possible, and
larger randomized clinical trials should be considered.
Cyclosporine A
The use of cyclosporine A (CsA), a calcineurin inhibitor, has
gained attention as treatment of SJS/TEN in recent years.
However, the data available rely on small open-label non-ran-
domized, mainly single-center case series. In a Spain-based
study, the outcome of 11 TEN patients treated with 3 mg/kg
bodyweight of CsA twice a day in an ICU burn unit [239] was
compared with six patients treated with IV cyclophosphamide
150 mg every 12 h plus corticosteroids at a dose of ≥ 1 mg/kg
per day of 6-methyl-prednisolone. In the CsA group, disease
progression stopped significantly more rapidly and there was
also faster complete wound healing.
In a French open, phase II trial including 10 SJS, 12 SJS/
TEN overlap, and 7 TEN patients, in 26 of 29 patients com-
pleting a 30-day treatment regimen with an initial dose of
3 mg/kg/day CsA no fatality was observed, although the pre-
dicted mortality rate was 2.75 [240]. The limitation of this
study was the fact that patients with renal failure, immune
deficiency, or a combination of both were excluded from the
analysis, and that the study control group consisted of a his-
torical cohort.
Clinic Rev Allerg Immunol (2018) 54:147–176
A promising effect of CsA could be shown in two Indian
studies. In the first study, where uncomplicated cases of SJS,
SJS/TEN overlap, or TEN were treated with 3 mg/kg/day CsA
during the first 7 days and subsequent tapering over the next
7 days, no deaths were observed [241]. In the second study,
where CsA 5 mg/kg/day was applied for 10 days, the observed
SMR of 0.32 in the CsA group was significantly lower com-
pared to the supportive treatment only group [242]. Similar
results were obtained in a patient collective in Singapore,
where CsA-treated patients showed a SMR of 0.42 [243].
Kirchhof et al. retrospectively analyzed the data of 64 pa-
tients receiving either 3–5 mg/kg/day CsA during the first
7 days, or 3 g/kg IVIG for 3 days [244]. The SMR in the
CsA group (n = 17) was 0.43 and 1.43 in the IVIG group
(n = 37), respectively. A recent study as well as a meta-
analysis performed in two burn units in Madrid by the same
authors analyzed the effect of CsA in patients with TEN com-
pared to TEN patients receiving other therapies [245]. In this
study, not only patients from the two Madrid burn units but
also patients with epidermal necrolysis from other centers in
Spain were included. Of 86 patients investigated, 49 patients
received CsA, 22 patients received other therapies, and 15
patients received IVIG. The applied observed vs expected
mortality rate based on SCORTEN was 0.42 for the CsA
group, 1.09 for the patient group treated with other therapies,
and 1.4 for IVIG group. Based on these data, the authors
conclude that the use of CsA has a benefit in epidermal
necrolysis. The meta-analysis including data of previous stud-
ies as well as the present study showed a mortality risk ratio
(MRR) of 0.14 for CsA-treated patients [245].
The effect of combined plasmapheresis and CsA in the
management of TEN was investigated at the burn unit of the
University of Bari [246]. According to the protocol, patients
received IV CsA at a dose of 250 mg/day in adult and 4 mg/kg
bodyweight/day in pediatric patients for 15 days and seven
cycles of plasmapheresis. The predicted mortality rate based
on SCORTEN being 58.3%, patients receiving combined ther-
apy had a significantly lower mortality rate of 8.3%, corre-
sponding to one of 12 patients analyzed.
In children, the use of IVIG and corticosteroids is contro-
versial as well [247–249]. In line with the observations in
adults, a recent case series in children with SJS/TEN treated
with CsA showed promising results suggesting its use as a
monotherapy [250]. Another recent prospective observational
study investigating adults and children found that plasmaphe-
resis may be superior to conventional therapies, also when
used alone [251].
Other Therapies
Cyclophosphamide and thalidomide, formerly used for the
treatment of SJS/TEN, are no longer used due to ineffective-
ness or higher mortality rate [239, 252].
Clinic Rev Allerg Immunol (2018) 54:147–176
All of 10 patients, treated with etanercept in a small uncon-
trolled case-series survived without relevant side-effects, the
average wound-healing time being 8.5 days [253]. However,
promising results with other TNF-α antagonists could so far
be documented in single cases only [254–257]. It is therefore
too early to draw any conclusions as to the effectiveness and
side-effects of TNF-α antagonists used in the treatment of
TEN.
Although therapeutical advances were made, due to
the severity of SJS/TEN randomized placebo-controlled
studies are not feasible. Therefore, data collection of
several centers is warranted for standardization and bet-
ter comparison.
Conclusions
This review summarizes current knowledge on diagnostics,
drugs implicated in SJS/TEN, and complications as well as
recent advances in the field of epidemiology, severity assess-
ment, genetics, pathophysiology, and treatment.
Depending on the collective analyzed the incidence of SJS/
TEN is between approximately 1 to 10 per million inhabitants.
Mortality may be as high as 20 to 30%. An important inde-
pendent risk factor for SJS/TEN is HIV infection.
In order to assess severity of SJS/TEN SCORTEN was
found to be superior to other scoring systems. For the identi-
fication of the most probable culprit drug, the ALDEN score is
used. Additionally, determination of serum granulysin and
FasL may be helpful as well as cytokine analyses.
A strong correlation of HLA-B*1502 is known in different,
but not all Asian ethnicities. Allopurinol-induced SJS/TEN is
strongly linked to HLA-B*5801 in several Asian populations
as well as in Caucasians, though to a lower extent. Apart from
HLA-dependent and HLA-independent genetic factors, other
variants, e.g., metabolic enzymes like GSTM1, have to be
considered as complementary factors.
The role of drug-specific cytotoxicity mediated by T cells,
genetic linkage, TCR restriction, and cytotoxicity mechanisms
in SJS/TEN is quite clear. By contrast, the role of other factors
like FasL in keratinocytes remains controversial. However,
CD14+ monocytes at the dermoepidermal junction might con-
tribute to enhanced CD8+ cell cytotoxicity. Also, granulysin
found in cytotoxic lymphocytes and NK cells triggers epider-
mal necrosis.
As to treatment, corticosteroids bear a high risk for bacte-
rial infections/sepsis and do not seem to be superior to sup-
portive care only. The sensitivity analysis based on multiple
studies shows a trend towards a beneficial effect of IVIG with
respect to mortality. CsA seems to be a promising therapy
though it is not an option for patients with renal failure and/
or immune deficiency.
167
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Informed Consent When necessary, informed consent has been col-
lected from patients.
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