Erythema multiforme is a distinctive clinical pathological entity with a wide variety of underlying causes.
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
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. When
the eruption is extensive, there may be severe oral mucosal involvement which defines Stevens-Johnson
syndrome, in which extensive skin necrosis is reminiscent of toxic epidermal necrolysis. There are rare
reports of erythema multiforme following allergic contact deratitis with nickel and poison ivy (i.e.Rhus
In those cases 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
In contrast, cases of drug-based etiology show a less intense dermal-based inflammatory cell infiltrate with
more pronounced degenerative epithelial changes including discrete zones of confluent epidermal 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, whereby keratinocytes
acquire an elongate cigar-shaped morphology with a hypereosinophilic condensed cytoplasm and pyknotic
elongated nuclei. Lesions of active herpes not infrequently show areas of interface dermatitis resembling
erythema multiforme. Characteristic viral cytopathic changes of herpes however is observed.
The main consideration is that of acute collagen vascular disease. In our experience, in lesions of
systemic lupus erythematosus or dermatomyositis, the presence of striking dermal mucin deposition is a
helpful distinguishing feature. 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 present in lesions 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, 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 as a function
the transient and acute nature of erythema multiforme is the unaltered architecture of the epidermis with
preservation of the retia, in contrast to collagen vascular disease, where 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 mulitforme unless, of course, there is unrelated liver disease.
Autoimmune progesterone dermatitis is temporally associated with the menstrual period. 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 an infectious agents including Mycoplasma pneumoniae, 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. Drug-induced forms of erythema multiforme can be quite severe,
and may be compatible with Steven-Johnson syndrome or the most severe variant of erythema multiforme,
designated as toxic epidermal necrolysis. A viral etiology is rarely implicated for these two severe forms
of erythema multiforme.
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 repetoire in such patients is composed
primarily of v beta 2 chain positive cells, suggesting a selective homing of lymphocytes to sites of viral
Recently antibodies directed against desmosomal plaque proteins desmoplakin I and II have been described in
a subset of patients with erythema multiforme major. 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.
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