COMMENTARY

of the disease, using CD8þCD28eIL- costimulated T lymphocytes from patients with Nearly a century ago, Stevens and
13þ T cells as a biomarker to guide systemic sclerosis trigger collagen production in Johnson described what is now
fibroblasts. Arthritis Rheum 2013;65:481e91.
treatment may also be useful. known as the Stevens-Johnson syn-
Li G, Larregina AT, Domsic RT, Stolz DB,
Medsger TA, Lafyatis R, et al. Skin-resident
drome (SJS) (Heng et al., 2015;
CONFLICT OF INTEREST
The authors state no conflict of interest. effector memory CD8þ CD28 T cells exhibit Roujeau et al., 1995). More than 60
a profibrotic phenotype in patients with sys- years ago, Lyell described epidermal
temic sclerosis. J Invest Dermatol 2017;137: necrolysis (Heng et al., 2015; Su
REFERENCES 1042e50.
et al., 2017). Most of the progress in
Fagnoni F, Vescovini R, Mazzola M, Bologna G, O’Reilly S, Ciechomska M, Cant R, van Laar JM.
Nigro E, Lavagetto G, et al. Expansion of cyto- Interleukin-6 (IL-6) trans signaling drives a
defining the spectrum of disease now
toxic CD8þ CD28 T cells in healthy ageing STAT3-dependent pathway that leads to hyper- known as SJS, overlap syndrome, and
people, including centenarians. Immunology active transforming growth factor-b (TGF-b) toxic epidermal necrolysis (SJS/TEN)
1996;88:501e7. signaling promoting SMAD3 activation and and differentiating it from other acute
Fenoglio D, Battaglia F, Parodi A, Stringara S, fibrosis via Gremlin protein. J Biol Chem
2014;289(14):9952e60. blistering diseases of skin and mucous
Negrini S, Panico N, et al. Alteration of Th17
and Treg cell subpopulations co-exist in pa- membranes has occurred during the
O’Reilly S, Ciechomska M, Fullard N,
tients affected with systemic sclerosis. Clin Przyborski S, van Laar JM. IL-13 mediates last 30 years. Over these three de-
Immunol 2011;139:249e57. collagen deposition via STAT6 and microRNA- cades, the causes, pathophysiology,
Fuschiotti P, Larregina AT, Ho J, Feghali- 135b: a role for epigenetics. Sci Rep 2016;6: and treatment of SJS/TEN have been
Bostwick C, Medsger TA. Interleukin- 27325.
13eproducing CD8þ T cells mediate dermal
explored comprehensively, but the
Pendergrass SA, Lemaire R, Francis IP, Matthew
fibrosis in patients with systemic sclerosis. answers to many questions, including
Mahoney J, Lafyatis R, Whitfield ML. Intrinsic
Arthritis Rheum 2013;65:236e46. gene expression subsets of diffuse cutaneous the effects of treatment, remain
Fuschiotti P, Medsger TA, Morel PA. Effector systemic sclerosis are stable in serial skin elusive.
CD8þ T cells in systemic sclerosis patients biopsies. J Invest Dermatol 2012;132:1363e73. Much of the work in this area has
produce abnormally high levels of interleukin- Yang X, Yang J, Xing X, Wan L, Li M. Increased
13 associated with increased skin fibrosis.
been done by the investigative group at
frequency of Th17 cells in systemic sclerosis
Arthritis Rheum 2009;60:1119e28. is related to disease activity and collagen
Hôpital Henri Mondor in Paris, led by
Hügle T, O’Reilly S, Simpson R, Kraaij MD, Bigley V, overproduction. Arthritis Res Ther 2014; Prof Jean-Claude Roujeau and his col-
Collin M, et al. Tumor necrosis factore 16(1):R4. leagues for nearly 30 years. Roujeau
has also established numerous inter-
national collaborations, including
See related article on pg 1065 ones with investigators at the Univer-
sity Medical Center in Freiburg, Ger-
many, and investigators in Taiwan. This
Stevens-Johnson Syndrome international group’s recent joint effort
assesses IL-15 levels in SJS/TEN (Su
and Toxic Epidermal Necrolysis: et al., 2017). The paper by Su et al.
(2017) in the current issue of JID
Associations, Outcomes, and demonstrates an association between
IL-15 levels and the severity and mor-
Pathobiology—Thirty Years of tality of TEN. This work takes another
step in illuminating the complex
Progress but Still Much to Be Done pathobiology of this disease. It may
also provide a basis for new and much
Robert S. Stern1 and Sherrie J. Divito2 needed treatment. Su et al.’s paper is
best understood in the context of the
Although rare, Stevens-Johnson syndrome and toxic epidermal necrolysis progress made over the last three de-
remain among the most devastating of acute conditions involving the skin. In the cades in identifying:
past 30 years, tremendous progress has been made in understanding the causes
and pathobiology of this often life-threatening condition. Su et al demonstrate 1. The clinical spectrum of SJS/TEN
associations between IL 15 serum levels and the outcome of patients with 2. Etiology
Stevens-Johnson syndrome and toxic epidermal necrolysis. Their findings pro- 3. Pathobiology
vide ideas for further investigations that may help us better understand the role 4. Outcome prediction
of cytokines in this T-cell mediate disease and provides clues to possible new 5. Methods of prevention
therapies. 6. Novel treatments.
Journal of Investigative Dermatology (2017) 137, 1004e1008. doi:10.1016/j.jid.2017.01.003
The clinical spectrum of SJS/TEN
For any prognostic test to be useful, the
1 2
Beth Israel Deaconess Medical, Boston, Massachusetts, USA; and Brigham and Women’s Hospital
disease to which it is applied must be
Ringgold Standard Institution—Dermatology, Boston, Massachusetts, USA defined precisely, that is, there should
Correspondence: Robert S. Stern, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, GZ522, be a close to as possible gold standard
Boston, Massachusetts 02215-5400, USA. E-mail: rstern@bidmc.harvard.edu definition of that condition. More than
ª 2017 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. 40 years ago, clinical, bacteriologic,

1004 Journal of Investigative Dermatology (2017), Volume 137


and histologic criteria defined staph
scalded skin syndrome and differenti-
ated it from what we now know as TEN.
Thirty years ago, there was little con-
sistency in the diagnostic criteria for
erythema multiforme and SJS. Over
these three decades, the understanding
that SJS and TEN are a spectrum of
disease, which vary in extent of
epidermal detachment and severity, but
have common pathology and etiology,
has become widely accepted.
Under Roujeau’s leadership, the
International SJS study developed and
validated diagnostic criteria that pro-
vide relatively precise diagnostic
criteria for SJS and TEN. This work also
defined erythema multiforme, which
differs from SJS/TEN clinically, demo-
graphically, and etiologically (Bastuji-
Garin et al., 1993).
Su et al.’s work confirms that the
population cytokine profile of SJS/TEN
is different from that of “mac-
ulopapular” drug eruptions, drug rash
with eosinophilia and systemic symp-
toms (DRESS) syndrome, and viral ex-
anthems. They also found higher serum
levels of IL-6, granulysin, and tumor
necrosis factor-a among those who
were diagnosed with TEN, the more
severe diagnosis within the SJS/TEN
spectrum. However, concentrations of
these cytokines varied greatly among
the patients tested, and they are un-
likely to be helpful additions to the
clinical examination in differentiating
SJS from TEN.
Etiology
With clinical and histologic criteria that
differentiate SJS/TEN from other condi-
tions, more robust epidemiologic
studies became possible. Pioneering
case series from Hôpital Henri Mondor
demonstrated that in substantial major-
ity of patients SJS/TEN could be attrib-
uted to drugs (Guillaume et al., 1987).
At the same time, interest in severe
adverse cutaneous reactions to drugs
increased among regulatory authorities
and pharmaceutical industries.
Working with colleagues in Europe
and the United States, Roujeau led in
organizing the International SJS/TEN
study, the first large case-control study
of drugs as a cause of this spectrum of
disease (Roujeau et al., 1995). This and
subsequent international collaborations
have identified the drugs most
frequently associated with the devel-
opment of SJS/TEN, as well as the usual
timing between beginning a likely
causative agent and the development
of first symptoms of SJS/TEN
(Mockenhaupt et al., 2008). Analyses of
these data indicate that drugs are
responsible in most patients with SJS/
TEN, but that a substantial minority of
times SJS/TEN is attributable to expo-
sures other than medications (Heng
et al., 2015; Sassolas et al., 2010).
Pathobiology
Because of their rarity, early and sub-
sequent samples of SJS/TEN are infre-
quently available for analysis.
Furthermore, an animal model that
reliably recapitulates human disease
does not exist. As a result, knowledge
about the pathobiology of SJS/TEN re-
mains elusive. However, ample evi-
dence points toward T-cell-mediated
and, to a lesser extent, natural killer-
(NK-)cell- mediated pathogenesis. Blis-
ter fluid from patients with SJS/TEN
contains T cells, primarily CD8þ type,
with lower numbers of NK and natural
killer T (NKT) cells. These cells
demonstrate target cell killing in vitro
(Chung et al., 2008). Also, several well-
characterized HLA associations have
been identified that predispose patients
to specific delayed-type drug hyper-
sensitivity reactions, including SJS/TEN
(White et al., 2015). Most of the
known HLA associations are class I,
supporting the role of CD8þ T cells
in the disease (White et al., 2015).
CD8þ T cells isolated from peripheral
blood of patients with SJS/TEN due
to carbamazepine were shown to
release the cytotoxic mediator gran-
ulysin in vitro in response to that drug.
These T cells also expressed a dominant
clone, indicating antigen-specific
expansion (Ko et al., 2011). No such
cells were found in patients who toler-
ated carbamazepine without disease
(Ko et al., 2011).
However, the mechanism of T-cell-
mediated pathogenesis is not certain.
Both CD8þ T cells and NK cells kill
target cells via release of granules
containing the cytotoxic molecules
perforin, granzymes, and granulysin,
via granule-independent secretion of
granulysin, or via expression of Fas
ligand (L), which binds Fas on target
cells, with resulting target cell (in this
COMMENTARY
case, keratinocyte) apoptosis. Initial
studies have pointed toward Fas:FasL-
mediated cytotoxicity in TEN (Viard
et al., 1998), but more recently gran-
ulysin, which is expressed highly in
skin biopsies and blister fluid from pa-
tients during active disease, has been
implicated as the major driver in
epidermal death. Also, injection of
granulysin into mouse skin induces
blistering lesions and necrosis similar to
that of SJS/TEN (Chung et al., 2008).
The involvement of cytotoxic CD8þ T
cells and NK cells suggests that IL-15, a
cytokine critical in CD8þ T-cell and
NK-cell development, survival, and
function, could play a major role in the
disease.
IL-15 is a widely expressed, pleio-
tropic cytokine produced by many cell
types, including immune cells (mono-
cytes, macrophages, and dendritic
cells) and nonimmune cells such as
keratinocytes (Fehniger and Caligiuri,
2001). In addition to its effects on T
and NK cells, IL-15 also modulates B
cells, monocytes, macrophages, den-
dritic cells, mast cells, and neutrophils
(Patidar et al., 2016). IL-15 is a member
of the common gamma chain (gc)
cytokine family, as its heterotrimeric
receptor shares one of its three sub-
units, gc, with a number of other cyto-
kines, IL-2, IL-4, IL-7, IL-9, and IL-21. It
shares a second subunit, the IL-2/IL-15
receptor b (IL-15Rb), with IL-2, and it
has a third, unique subunit, IL-15Ra
(Figure 1) (Jabri and Abadie, 2015). IL-
15 exists in three functional forms:
soluble IL-15, soluble IL-15:IL-15Ra
complex, and membrane-bound IL-
15:IL-15Ra complex (Figure 1). The last
form, membrane-bound IL-15:IL-15Ra,
is the most common and effective form
for IL-15 presentation (termed trans-
presentation) (Jabri and Abadie, 2015).
In this form, the membrane-bound
complex engages the IL-15Rb/gc het-
erodimer expressed on the surface of a
receiving cell. Cis-presentation of the
soluble IL-15 or soluble IL-15:IL-15Ra
complex to receiving cells does occur,
but this is believed to be of lesser
importance for immune responses (Jabri
and Abadie, 2015).
IL-15 signals through the Janus
kinase-signal transducer and activator
of transcription (JAK-STAT) pathway,
with the gc subunit activating JAK 3,
then in turn STAT5, and the IL-15Rb
www.jidonline.org 1005
 COMMENTARY

Figure 1. IL-15 presentation and receptor binding. IL-15 is presented most effectively in trans, meaning complexed to membrane-bound IL-15Ra. This
membrane-bound complex on the surface of an IL-15-producing cell binds to IL-15R homodimer, consisting of IL-15Rb and gc subunits expressed on the surface
of CD8þ T cells or NK cells. Alternatively, soluble IL-15 complexed to soluble IL-15Ra can bind to the same receptor homodimer, or soluble IL-15 can bind the
heterotrimeric receptor, consisting of IL-15Ra, IL-15Rb, and gc subunits expressed on the surfaces of CD8þ T cells or NK cells. Binding of IL-15 to its receptor
induces signaling via the gc subunit to Janus kinase (JAK) 3, which, in turn, stimulates STAT 5, and the IL-15Rb subunit to JAK 1, which, in turn, stimulates STAT
3. NK, natural killer; STAT, signal transducer and activator of transcription.

subunit activating JAK1, then in turn
STAT3 (Jabri and Abadie, 2015). Multi-
ple downstream signaling pathways are
stimulated, including the phosphoino-
sitide 3-kinase/acutely transforming
retrovirus AKT8 in rodent T-cell lym-
phoma/mechanistic target of rapamycin
(mTOR) pathway, which appears crit-
ical for IL-15-mediated effects on NK
cells (Ali et al., 2015) and T cells
(Powell and Delgoffe, 2010).
IL-15 promotes T- and NK-cell
responses both directly and indirectly
(Figure 2). It directs T-cell development,
expansion, and maintenance/survival,
particularly of CD8þ memory T cells,
and it acts as a chemoattractant
(Fehniger and Caligiuri, 2001). It also
stimulates T cells to produce proin-
flammatory cytokines/chemokines and
to increase cytotoxicity (Jabri and
Abadie, 2015). IL-15 orchestrates NK-
cell development, expansion, survival,
and activation (Fehniger and Caligiuri,
2001). It also contributes to the ho-
meostasis and expansion of NKT cells
(Fehniger and Caligiuri, 2001), a subset
of T cells, found in blister fluid of pa-
tients with SJS/TEN, that recognize
CD1d rather than traditional major his-
tocompatibility complex. IL-15 activates
dendritic cells and macrophages,
resulting in increased antigen presenta-
tion to T cells and production of proin-
flammatory cytokines, which drive the
adaptive immune response (Jabri and
Abadie, 2015; Patidar et al., 2016).
To our knowledge, Su et al. are the
first to demonstrate a substantive link
between IL-15 and SJS/TEN. They show
that IL-15 levels correlate with disease
severity and mortality, implicating IL-15
as a possible mediator of disease. They
demonstrate that the addition of exog-
enous IL-15 stimulates TEN blister fluid
cells to secrete granulysin in three
samples and that neutralization of IL-15
reduces drug-induced stimulation of
cells from a patient with TEN. Further
work is needed to determine whether
IL-15 drives T- and NK-cell responses in
SJS/TEN.
The current study measured soluble
IL-15 in serum, although trans-presen-
tation of IL-15, that is, membrane-
bound IL-15 in immunologic synapses
with receiving cells, may be more
important for driving immunologic re-
sponses. Expression of IL-15 in skin, as
well as activation of downstream
signaling events to confirm IL-15 ac-
tivity, should be investigated. The
discrepancy between serum levels and
extent of tissue damage is relevant to
SJS/TEN as granulysin levels in serum
have not shown consistent correlation
with disease severity or mortality
(Chung et al., 2008; Su et al., 2017), but
granulysin levels within blister fluid
did correlate with disease severity
(Chung et al., 2008). Lymphocyte
stimulation tests in SJS/TEN have also
been inconsistent. For example,
Porebski et al. (2013) attempted to
enhance responses to lymphocyte
stimulation tests by adding exogenous
IL-7 and IL-15 but found these cyto-
kines to be effective in only a few pa-
tients. Ultimately, blocking IL-15 in
patients or in an animal model of SJS/
TEN with prevention/resolution of dis-
ease is likely to be necessary to support
a primary causative role for IL-15.
Predicting outcomes
Early work at Hôpital Henri Mondor
identified factors associated with
death among patients with TEN (Revuz
et al., 1987). Subsequently, this group
developed a specific severity of illness
score (SCORTEN) for cases of TEN,
which was shown to be a good pre-
dictor of survival for these patients
with SJS/TEN (Bastuji-Garin et al.,
2000).
SCORTEN incorporates seven inde-
pendent prognostic factors. Only one of
these, body surface area involved
(10%), is related directly to the area
detachment. Age (>40) and physiologic
factors accounted for the remaining six
independent prognostic factors: age,
malignancy, tachycardia, serum urea,
serum glucose, and serum bicarbonate.
Some of these physiologic factors could
impact serum cytokine levels. Impor-
tantly, agreement between SCORTEN
values and mortality vary over the first 5
days of admission (Guegan et al., 2006).
Su et al.’s work demonstrates that a
number of factors, including IL-6, IL-8,

1006 Journal of Investigative Dermatology (2017), Volume 137

 COMMENTARY
AcƟvaƟon
Increased anƟgen presentaƟon
Increased pro-inflammatory cytokine producƟon

M DC

NKT IL-15 CD8+

Development
Expansion
Maintenance/Survival
Homeostasis ChemoaƩracƟon
Expansion AcƟvaƟon
?AcƟvaƟon Increased cytotoxicity
Increased cytokine/chemokine producƟon
NK

Development
Expansion
Survival
AcƟvaƟon
Increased cytotoxicity
Increased cytokine/chemokine producƟon

Figure 2. Pleiotropic effects of IL-15 on immune cells thought critical to SJS/TEN pathogenesis. IL-15 induces activation of skin antigen presenting cells,
including macrophages (MF) and DC. Activation enhances both the production of proinflammatory cytokines and antigen presentation. IL-15 promotes
development, expansion, and maintenance/survival of CD8þ T cells and NK cells. It also stimulates CD8þ T-cell and NK-cell activation, resulting in increased
cytotoxicity and cytokine/chemokine production. IL-15 plays a role in NKT-cell expansion and homeostasis although its effects on NKT-cell activation are still
under investigation. DC, dendritic cells; NK, natural killer cells; NKT, natural killer T cells; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

tumor necrosis factor-a, and most
notably IL-15, were upregulated in pa-
tients with SJS/TEN. In Supplementary
Figures S3, S4, and S5, the authors also
present data that strongly suggest an
association between the evolution of
individual patients’ clinical course,
extent of cutaneous involvement, and
IL-15 levels. However, these findings
raise questions about the utility of IL-15
levels in determining prognosis.
Prognosis implies a forecast of the
likely course or outcome of the disease.
As noted above, SCORTEN is such a
validated measure, with good perfor-
mance characteristics based on the area
under its receiver operator characteris-
tics curve. Comparable data are not
presented for IL-15. However, the data
presented do suggest that only a few of
the patients who died had notably high
initial IL-15 levels. The majority of
those with high IL-15 levels also had
SCORTEN values equal to 3 or greater,
values associated with high mortality
(Bastuji-Garin et al., 2000; Guegan
et al., 2006). Many individuals who
died had only modest initial IL-15
levels, suggesting that early in the dis-
ease this cytokine may not be a sensi-
tive predictor of mortality.
Although only presented for a limited
number of patients (see Su et al.’s sup-
plementary figures), an individual’s IL-
15 serum level over time does seem to
be correlated with clinical course and
outcome. Additional data may show
that clinical worsening or mortality is
predicted better on the basis of changes
in IL-15 levels rather than as a single
value. In an individual patient, the
apparent correlation of IL-15 levels
over time with clinical status does
provide evidence that IL-15 may play
an important role in SJS/TEN.
Prevention
Although case-control and registry
studies have identified the medications
with highest associated risk for SJS/TEN
and patient characteristics with higher
risk for these reactions, the absolute risk
of most medications in most pop-
ulations is quite low. However, there
are notable exceptions. Perhaps the
most striking example is the identifica-
tion of specific HLA determinants that
are associated with a greatly increased
risk of SJS/TEN in Han Chinese who
receive carbamazapines (Chung et al.,
2004). This landmark research
changed prescribing practices and
provided hope that genetic screening
could greatly reduce the risk of these
reactions with other drugs and in other
populations. Unfortunately, subsequent
genetic studies have revealed that such
strong associations are limited to
certain drugs and in certain populations
(Lonjou et al., 2006).
Treatment
Prompt withdrawal of causative drugs,
followed by supportive care, remains
the mainstays of treatment (Garcia-
Doval et al., 2000; Roujeau et al.,
2011). The association of higher IL-15
levels with patients’ clinical courses
(and mortality) suggests that IL-15 may
be another therapeutic target for treat-
ment of this often fatal disease. How-
ever, past experience with targeted
therapies has largely been disap-
pointing. Tumor necrosis factor-a is
increased in SJS/TEN. One of the
few randomized placebo-controlled
studies of a therapy for SJS/TEN
examined the effect of thalidomide, a
potent inhibitor of tumor necrosis fac-
tor-a, on mortality. The group treated
with thalidomide experienced higher
death rates (Wolkenstein et al., 1998).
Initial enthusiasm for many treatments

www.jidonline.org 1007
 COMMENTARY
including intravenous immunoglobulin,
a targeted therapy for SJS/TEN, has also
waned as more recent evidence sug-
gests that most treatments have had
little or no effect on outcome (Roujeau
et al., 2011). If its correlation with
clinical course is more robustly
demonstrated, IL-15 may be a thera-
peutic target, and monitoring IL-15
levels may provide a useful surrogate
endpoint for evaluating treatments.
If IL-15 is, indeed, a
major cytokine
orchestrating SJS/TEN,
a number of novel
therapeutics hold
promise for efficacy in
a disease that desper-
ately requires useful
treatment options.
Tofacitinib and ruxolitinib are novel
JAK-STAT inhibitors that inhibit JAK 1
and 3 and JAK 1 and 2, respectively.
Tofacitinib has FDA approval for rheu-
matoid arthritis, and ruxolitinib is
approved for myelofibrosis and poly-
cythemia vera. Both are under investi-
gation for cutaneous inflammatory
disorders such as psoriasis, alopecia
areata, and vitiligo. Several new JAK
inhibitors are under development or
already in clinical trials. There is a
humanized monoclonal antibody that
blocks IL-15Rb, termed Hu-Mik-b-1,
currently in clinical trials for T-cell
large granular lymphocytic leukemia
(Waldmann et al., 2013), human
t-lymphotropic virus 1-associated
complications (Clinical Trials.gov
NCT00076843) and refractory celiac
disease (Waldmann, 2013). Alterna-
tively, because IL-15 activates the mTOR
pathway, which, in turn, promotes NK-
and T-cell responses, mTOR inhibitors
such as sirolimus or everolimus could
theoretically mitigate SJS/TEN.
The work from the Taiwanese,
French, and German group demon-
strates the power of international
cooperation in the study of SJS/TEN, a
rare but devastating condition. Given
the limited resources that have been
available for research in this area, the
progress made in defining SJS/TEN,
1008 Journal of Investigative Dermatology (2017), Volume 137
determining its most frequent causes,
understanding its pathobiology, and
evaluating its treatment has been
exceptional. It should be noted that
Prof Jean-Claude Roujeau’s ideas and
contributions are evident in much of
the most important work done in this
area of inquiry over the last 30 years.
CONFLICT OF INTEREST
RS has served as a consultant for BMS, Mylan,
Bayer, Plexxicon, Hydra Biosciences, the US
Department of Justice, and the University of Vir-
ginia. SJD states no conflict of interest.
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