Toxic Epidermal Necrolysis/Stevens Johnson Overlap Syndrome Triggered by Exotic Wood Exposure
Cynthia M. Magro
Weill Medical College of Cornell University
New York, New York
Reactive Cytotoxic CD8 Interface Dermatitis
I have selected three cases of reactive interface dermatitis whereby the antigenic triggers and
clinical circumstances resulting in these striking presentations are varied. I would like to first of
all consider in brief a broad overview of the morphologic pattern that more or less defines these three
cases namely a relatively cell poor vacuolar pattern of interface dermatitis. The varied
pathogenetic mechanisms that lie behind this form of interface dermatitis are explored.
The definition of cell-poor vacuolar interface dermatitis is a morphologic one and it is
characterized by basilar keratinocyte and subepithelial vacuolopathy unaccompanied by a significant
inflammatory cell infiltrate. Usually, there is a component of lymphocyte tagging along the
dermal-epidermal junction pointing to the immunopathogenetic basis, namely, one of type IV cellular
cytotoxicity. In a dermatosis that falls under the general rubric of a cell poor interface dermatitis it
is not uncommon to see areas of interface dermatitis that have a more lichenoid morphology. This may be
either in the context of a type 4 immune reaction or reflective of antibody dependent cellular
cytotoxicity. Traditionally a true type IV cytotoxic immune response is a cutaneous reaction pattern e
that one associates with an exogenous trigger such as drug while antibody dependent cellular immunity
would indicate a connective tissue disease diathesis. It is very difficult at a light microscopic level
to distinguish between a true type IV cytotoxic immune response and one initiated by antibodies.
Although we traditionally consider cutaneous manifestations of collagen vascular disease in the context
of being antibody mediated a role for true cellular immunity may also be operational .
The differential diagnoses of a cell-poor interface dermatitis is broad and includes:
While the aforesaid diagnostic considerations are specific clinical and pathological entities, in
general type IV immunologic response to circulating exogenous antigen and or antibody dependent cellular
immunity can be associated with vacuolar interface change along the dermal epidermal junction. Although
the morphologic end point of both type IV hypersensitivity and antibody dependent cellular immunity is
remarkably similar, namely one of lymphocyte apposition to keratinocytes with the subsequent induction
of keratinocyte injury the pathogenetic mechanisms are different.
- erythema multiforme and related conditions specifically in the context of Stevens Johnson syndrome,
toxic epidermal necrolysis and fixed drug eruption.
- graft-versus-host disease
- a morbilliform viral exanthum
- a morbilliform drug reaction
- collagen vascular disease specifically in the context of lupus erythematosus,
dermatomyositis, and mixed connective tissue disease
The three cases I have chosen are varied in their clinical presentation and the etiologic trigger
although the way in which epithelial injury occurs is the same namely in the context of a cytotoxic CD8 T
In other forms of interface dermatitis including certain forms of collagen vascular disease such as
subacute cutaneous lupus erythematosus and dermatomyositis and the early phase of lichen planus and graft
versus host disease, the main cell infiltrating the epidermis may be the CD4 lymphocyte. The
contribution of the CD4 lymphocyte to frank epithelial injury is less defined.
Toxic Epidermal Necrolysis/Stevens Johnson Overlap Syndrome Triggered by Exotic Wood Exposure
This patient's case presentation serves as a prototypic example of a rare but severe form of type IV
hypersensitivity falling under the designation of Stevens Johnson Syndrome(SJS). In the vast majority of
cases the inciting trigger is of drug based etiology although in this case the apparent antigen was of
unquestionable contactant based etiology. There has been confusion in the literature regarding the
differences if any existing between erythema multiforme and SJS/Toxic epidermal necrolysis(TEN). The
distinction of TEN from SJS is based on the extent of cutaneous involvement with greater than 30% skin
necrosis being characteristic for TEN. In SJS the extent of mucosal involvement is marked and
cutaneous necrosis is usually less than 10% of the total body surface area. There are cases which
exhibit an overlap between SJS and TEN whereby the cutaneous necrosis is between 10 and 30%. In the
past, SJS and TEN were considered under the designation of erythema multiforme major while other forms of
erythema multiforme fell under the appellation of erythema multiforme minor. This arbitrary designation
of EM minor versus major is no longer the preferred nomenclature as there is enough pathophysiologic
evidence to suggest certain differences although in each the inciting trigger is an immunologic response
to an exogenous antigen. The antigen is varied and whether one is dealing with EM, TEN or SJS the
immune response to the antigen is considered idiosyncratic. Specifically only a small subset of people
develops an immune response to a specific antigen that will manifest as EM, SJS, and or TEN.
Erythema multiforme represents the most common form of cytotoxic epidermal hypersensivity encountered
from both a clinical and morphologic perspective and hence we will consider in detail its distinctive
features followed by a brief review of SJS and TEN with a consideration regarding their pathogenesis.
I. Classic Erythema Multiforme
Erythema multiforme is a distinctive clinical and pathological entity whereby the trigger leading to
its development is varied. From a clinical perspective, the classic lesion has a targetoid morphology
with a peripheral rim of erythema and a central zone of pallor. Some lesions may manifest a dusky or
violaceous appearance with no true central clearing. Blisters may be observed. As the pathogenetic
basis of erythema multiforme is one of cellular cytotoxicity, the morphologic sites of predilection are
those where antigenic processing is maximal, which includes the palms and soles, however, the lesions can
become widespread. The disease is typically self-limited but it may recur. There are rare reports of
erythema multiforme following allergic contact dermatitis with nickel and poison ivy (i.e.Rhus
dermatitis). The concept of a contactant in the induction of erythema multiforme is not well known but
it clearly occurs.
In those cases of erythema multiforme which are mediated by infection, one typically observes a fairly
brisk angiocentric superficial and deep lymphocytic infiltrate along with a cell-poor interface
dermatitis with minimal epidermal injury. In contrast, drug-based erythema multiforme show a less
intense dermal-based inflammatory cell infiltrate with more pronounced epithelial necrosis. Focal
small areas of basilar vacuolopathy accompanied by lymphocyte tagging along the dermal-epidermal junction
are the hallmarks; suprabasilar lymphocytosis around degenerating keratinocytes may also be seen. In
drug-based erythema multiforme, acrosyringeal accentuation of these interface inflammatory and
degenerative epithelial changes is typical and streak dyskeratosis is demonstrated. The latter refers to
the acquisition of a distinctive keratinocyte morphology whereby keratinocytes demonstrate an elongate
cigar-shaped morphology with a hypereosinophilic condensed cytoplasm and pyknotic elongated nuclei. Such
cells may or may not be accompanied by lymphocyte satellitosis. Lesions of active herpes show areas of
interface dermatitis resembling erythema multiforme. Characteristic viral cytopathic changes of herpes
however are observed.
The main consideration is that of acute collagen vascular disease and acute graft verus shost
disease. In our experience, in lesions of systemic lupus erythematosus or
dermatomyositis, the presence of striking dermal mucin deposition is a
critical distinguishing clue that is present in most cases. As well, the degree of epithelial injury in
such cases is usually less than that observed in erythema multiforme. Acrosyringeal accentuation, as
seen in drug associated erythema multiforme, is not a typical feature of acute systemic collagen
vascular disease. While sparse tissue eosinophilia may be observed in drug associated erythema
multiforme, tissue eosinophilia in the setting of systemic collagen vascular disease is uncommon. In
erythema multiforme there usually is no alteration of the stratum corneum and or the epidermal thickness,
pointing to the transient and acute nature of the eruption. In contrast, in the interface dermatitis of
collagen vascular disease, hyper- and parakeratosis is frequent. Also in lesions of collagen vascular
disease one observes an atrophying interface dermatitis with retiform effacement.
The distinction of erythema multiforme from acute graft versus host disease may be difficult. A
recent study demonstrated that intraepidermal bile pigment deposition can be seen in biopsies of graft
versus host disease and correlates with hyperbilirubinemia and or liver involvement. While this finding
is only observed in a minority of cases of graft versus host disease (i.e. 6% of biopsies) it is a highly
specific finding; it is not observed in erythema multiforme unless, of course, there is unrelated liver
Autoimmune progesterone dermatitis is temporally associated with the menstrual period and may also
have its onset during pregnancy. The manifestations are polymorphous and include urticaria, erythema
multiforme, and eczema. Histologically the cases show a variable histomorphology dependent on the
clinical presentation. Cases resembling erythema multiforme show a vacuolar interface dermatitis with
varying degrees of keratinocyte necrosis. During each cycle, the eruptions may appear at previously
affected sites, hence mimicking the clinical features of a fixed drug eruption. This rare phenomenon is
attributed to an autoimmune reaction to female sex hormones. The condition can improve with tamoxifen
which suppresses ovulation and the post-ovulation rise in endogenous progesterone levels. In extreme
cases an oophorectomy is performed
Erythema multiforme is a type 4 cellular cytotoxic reaction provoked by antigenic triggers which
include drugs and infectious agents including Mycoplasma pneumoniae, and
herpes simplex virus infection including in the context of recurrent herpes labialis. Typical target
lesions are more common in patients whose erythema multiforme is triggered by herpes simplex.
Herpes-associated erythema multiforme occurs in association with recurrent herpes simplex infection.
A recent study has shown herpes DNA polymerase gene(Pol) and pol gene expression, the latter through
immunohistochemistry using antibody directed against pol in lesional skin of patients with herpes
associated erythema multiforme. In addition the T cell receptor variable chain repertoire in such
patients is composed primarily of v beta 2 chain positive cells, suggesting a selective homing of
lymphocytes to sites of viral antigen
Recently antibodies directed against desmosomal plaque proteins desmoplakin I and II have been
described in a subset of patients with erythema multiforme. Such studies suggest a humoral based
etiology in the propagation of lesions of erythema multiforme in these patients. The epitope is
localized at the carboxy terminal domain of desmoplakin and is responsible for the assembly of keratin
filaments with desmosomes. Purified human antibody directed against the carboxy terminus of desmoplakin
1 and II when injected into newborn mice produces a constellation of changes that resembles erythema
multiforme, suggesting a role for these antibodies in a subset of patients with erythema multiforme.
II. Stevens Johnson Syndrome/toxic Epidermal Necrolysis
As a point of reiteration SJS/TEN represents an idiosyncratic type IV immune response to a drug
whereby the main implicated drugs are sulfasalzine, allopourinol, and nonsteroidal anti-inflammatory
drugs with the commonest class of drugs however are the sulfonamides. The main distinguishing features
which separate both SJS and TEN from EM is the severity of epithelial damage. In SJS the mucosal
involvement is striking and may extend to involve the respiratory tract and conjunctiva. Severe mucosal
involvement can also occur in TEN although in general the extent of mucosal involvement is greater in SJS
than in TEN. The difference between SJS and TEN is reflected by the extent of cutaneous involvement. In
SJS despite the massive epithelial injury the extent of cutaneous involvement is less than 10%. In TEN
the extent of skin involvement is more than 30%. Cases that exhibit between 10 to 30% body surface
involvement are designated as an SJS/TEN overlap. This patient(case 1) had a degree of skin involvement
along with severe mucosal disease to warrant the categorization as an SJS/TEN overlap. An exceptional
aspect of this case is the nature of the trigger which appeared to be an exotic wood. To add further to
the rarity of this extraordinary case is the fact that his coworker who came from the same town
developed a virtually eruption suggesting that he too was an idiosyncratic responder reflecting a common
genotypic predisposition in both of these individuals as will be alluded to presently. His coworker's
eruption was also compatible with an SJS/TEN overlap although in his case the administration of oral
prednisone was sufficient to eradicate his skin rash and prevent further progression. The goal of this
case is to review the known pathophysiology of SJS/TEN and the role of contactants in the evolution of
I: Decreased Ability to Metabolize the Active Allergen/Drug Metabolite
It has been shown that in patients with SJS and TEN, the drug reactive metabolites are produced in
excess due to the inability to adequately detoxify and or metabolize the drugs. Such patients are said
to be slow acetylators.
II. Haplotype Predisposition
In addition to this inability to adequately metabolize the drug hapten a certain HLA B genotype:HLA
B12,HLA B5801 and HLA B1502(Hans Chinese) selectively expressed on keratinocytes bind to the drug. The
HLA is divided into three basic groups : HLA-A, HLA-B, and HLA,C and represents class I major
histocompatibility antigens. These genes make proteins that are expressed on the surface of the cell
and bind foreign peptides that are extruded from the interior of the cell to the surface. This complex
is recognized as foreign and is then destroyed by the immune system. There are many normal variations of
the HLA B gene. Depending on the specific alleles will determine whether or not that particular HA-B
associated protein is recognized by a certain foreign peptide processed by the host cell. Hence there
are specific HLA alleles that are associated with severe drug reactions. For example the HLA-B*1502
is at greater risk for developing TEN in response to carbamazepine while the
HLA-B*5801, is associated with an increased risk of severe skin reactions in people treated with allopurinol. Among people with human immunodeficiency virus (HIV) infection, a version of HLA-B designated HLA-B*5701 is
associated with an extreme sensitivity to abacavir.
III. Dysregulated Progressive Apoptosis
Another unique aspect of TEN/ SJS is one of massive keratinocyte necrosis which far exceeds the extent
of lymphocyte infiltration. There are likely both in situ mechanisms operational in the induction of
keratinocyte injury as well as the role of soluble pro-apoptotic factors in the evolution of the
A. In situ factors promoting epithelial injury
The drug induces a clonal proliferation of cytotoxic CD8 T cells which express granzyme, a cytotoxic
protein which will induce keratinocyte injury. These antigenically responsive T cells are found both in
the peripheral blood and in an situ location with the target organ, namely the skin. These activated CD8
cells localized in the skin may also express Fas ligand which can bind to Fas normally expressed by
keratinocytes. If the extent of epithelial injury was to a large extent determined by the number of CD8
T cells localized to the skin the degree of epithelial injury which characterized TEN and SJS would not
occur however. There is a relatively disparity between the extent of T cell infiltration which can be
minimal and the degree of massive keratinocyte and epithelial injury. Hence there are likely additional
soluble distant factors which contribute to epithelial injury.
B. Soluble factors in the evolution of the epithelial injury
Soluble factors are likely operational in the evolution of SJS/TEN and may define a very important
mechanism of epithelial injury. These soluble factors include TNF, interleukin 6 and soluble CD40
Ligand. The actual soluble levels of Fas Ligand are significantly higher in patients with SJS/TEN.
Peripheral blood mononuclear cells from patients with SJS/TEN elaborate more Fas ligand. The basis of
using IVIG to treat SJS/TEN relates to potential neutralization of soluble Fas ligand and the blockage of
intracellular Fas signaling. Activation of FAS through FASL leads to diffuse apoptotic cell death. Fas
mediates death of epidermal cells in TEN. Fas L mediates apoptotic cell death by binding to FAS inducing
the activation of caspase enzymes. Fas is expressed in many cells including keratinocytes, hepatocytes
and peripheral blood mononuclear cells. Fas L is normally expressed by activated T cells and natural
killer cells. SJS derived peripheral blood mononuclear cells produce large quantities of soluble Fas
after stimulation with the implicated drug. All of these studies indicate that sensitized T cells
produce large quantities of Soluble Fas Ligand, an apparent major factor pathogenetically in the
evolution of SJS/TEN. The question arises as to why the peripheral blood mononuclear cells produce such
large quantities of Fas ligand. This anomaly may reflect a Fas ligand gene polymorphism. The result of
the Fas ligand gene polymorphism is enhanced elaboration of Fas ligand by activated peripheral blood
mononuclear cells. Localization of injury is organ specific reflecting high sensitivity end organ target
cells to Fas Ligand. If for example the end organ cell with high sensitivity to Fas ligand is the
hepatocyte the drug will evoke massive hepatic necrosis.
C. Other single nucleotide gene polymorphisms in the pathogenesis of TEN and SJS
It has been demonstrated that genetic alterations in the Il 13/Il-4R signaling pathway may regulate
Th1 or Th2 cytokine driven inflammatory mechanisms. In one study Japanese patients with SJS/TEN had
polymorphisms in the allergy related Il-4R gene and that the ratio of each allele in the polymorphisms
was the opposite of the ratio reported in atopy and asthma.
IV. Contactants as the Trigger to TEN/SJS
In regards to the literature precedent addressing contactants as a cause of TEN/SJS it is in the
context of small series and anecdotal case reports. What are the known contactants that can evoke TEN/
SJS ? Dendrimers have been implicated. There is one case report describing a student who handled
dendrimers in a chemistry lab and then developed targetoid plaques on the arms. The biopsy showed
typical changes of erythema multiforme. His rash progressed to diffuse exudative erythema and bullae
In addition he had coalescing bullae and a positive Nikolsky sign. The latter is demonstrated by
applying pressure on the skin resulting in the induction of lateral epidermal separation following light
pressure in an apparently normal appearing area of skin. There were some relevant lab findings which
included a low titer of serum complement and C3.
The rash improved on methylprednisolone IV 1000mg/day for 3 days followed by a gradual taper of
prednisone from 40/day. His rash relapsed whenever he reentered the laboratory. There are multiple
reports (case series of 15) reporting SJS/TEN-like reactions to dormex (hydrogen cyanamide), a growth
promoter of grapes including in the context of cleaning utensils which had been in contact with the
chemical developing a rash in 5 to 7 days. The rash had a specific prodrome of burning and stinging
followed by itchy, erythematous papules which subsequently progressed in targetoid and bullous lesions
and finally broad zones of epidermal denudement. A biopsy was typical for erythema multiforme. Rapid
resolution occurred within 7 days of treatment.
There is another reported case of 32 year old female who developed EM which quickly progressed to TEN
following double exposure to an applied perfume. The rash initially remained limited to the area
sprayed, neck, and appeared as blotchy erythema. Upon second exposure to the abdomen diffuse targetoid
lesions with bulla developed over her trunk and arms within a day. The biopsy was confirmatory of
SJS/TEN. Unfortunately the patient became infected and died of toxic shock in the setting of prednisone
and antibiotic therapy. Another reported case involved a 36 year old carpenter admitted for 5 days of
blisters and target lesions on the hands and forearms., much more on the left. Within three days the
rash spread to the neck, thighs and penis, with mucosal ulceration and conjunctivitis. Vesicles and
bullae were most conspicuous around the neck line and on the forearms. The patient was taking no
medications but mentioned that as a hobby he worked as a wood turner and had been in contact with
rosewood. He did remember that as he sanded the wood with his right hand the saw dust was sprayed on the
left arm. A patch test to saw dust was strongly positive with a blistering reaction at 96 hours. The
final case concerned a 25 year old Japanese woman, a luthier, developed intensely pruritic, red-bean
sized papulovesicles and erythema that started on palms and arms and then progressed to cover upper arms,
trunk, and ankles and coalescing into targetoid lesions which blistered with a positive Nikolsky skin.
The patient had handled Pao ferro. A biopsy was confirmatory of SJS. A patch test to Pao Ferro was
positive and continued for two weeks. There are 4 other reports of Pao Ferro EM/SJS like reactions and
in all cases biopsies were not consistent with a contact dermatitis and were indistinguishable from
EM/SJS from drug or infection.
In summation then contactants are a potential cause of SJS/TEN. The implicated contactants that can
induce this severe reaction are few in number and there may be pathophysioloogic basis. Dendrimers are
able to mimic biological molecules. Dormex is hydrogen cyanamide. Rosewood/Dalbergia latifolia or East
Indian rosewood have as active agents quinonoids of which 3,4-dimethoxydalbergione is the most potent
Pao ferro is also a quinonoid and essentially similar to rosewood
Macassar ebony and epoxy resins have effective compounds similar to those implicated in rosewood.
Cutaneous absorption or inhalation of an immunogenic chemical may provide some basis for contactants as
a potential trigger to SJS/TEN.
Concluding Remarks Regarding Contactant Triggered SJS/TEN
In summary then SJS/TEN is distinctive clinically and pathophysiologically. The differential
diagnosis would comprise erythema multiforme, generalized fixed drug eruption, severe acute graft versus
host disease, and a TEN - like presentation of paraneoplastic pemphigus and linear IgA disease.
The clinical history and light microscopic findings should allow distinction between these various
While one always must consider a drug based etiology there is the potential for other triggers
including contactant and infection. The distribution of the lesions and patient history might provide
clues. Some of these contactants are fairly common in certain professions. The basis of the potentially
life threatening epithelial injury an idiosyncratic allergic response to drug/contactant generating a
clonally responsive CD8 T cell population found in both the skin and peripheral blood responding to
antigen, large quantities of soluble Fas ligand released by sensitized C8 T cells reflecting a potential
gene polymorphism and a high sensitivity of the end organ cell expressing Fas to Fas ligand. Treatment
at the initial phases to bind soluble Fas ligand could emerge as an important tool in reducing injury.
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