Erythema
Multiforme, Stevens-Johnson Syndrome, And Toxic Epidermal Necrolysis
Erythema multiforme minor, erythema multiforme
major, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis are all
classified as hypersensitivity reactions, with the most common initiating event
being a medication or an infection. Some authors consider these to be
completely distinct entities with specific etiologies. Until that is proven, a
simple way of approaching these diseases is to consider them as representing a
continuum with varying degrees of muco- cutaneous involvement. Erythema
multiforme minor is the most likely of all these conditions to be a unique
entity, because it is more commonly caused by infection (e.g., herpes simplex
virus, Mycoplasma pneumoniae). It is also more commonly seen in
childhood. The other entities are much more likely to be initiated by
medications. Almost all types of medications have been reported to cause these
reactions, but a few classes account for most of these severe skin reactions.
The classes of medications most commonly implicated are antibiotics (especially
sulfa-based products), antiepileptics, allopurinol, and the nonsteroidal antiinflammatory
drugs (NSAIDs).
Clinical Findings: There is no racial or ethnic pre-dilection, and
males and females are equally affected. For unknown reasons, patients with
coexisting human immunodeficiency virus (HIV) infection are much more likely to
develop a serious drug eruption than HIV-negative controls. The pathomechanism
of this reaction is poorly understood.
Erythema multiforme minor is the
most frequently seen of these eruptions. It is more common in children and
young adults and can be caused by a myriad of infections and medications.
Exposures to topical anti- gens such as urushiol in the poison ivy plant have
also been reported to cause rashes resembling erythema multiforme minor. The
most common cause that has been isolated is the herpes simplex virus. The rash
of erythema multiforme minor can be seen in association with a coexisting
herpesvirus infection or independent of the viral infection. Most episodes last
for 2 to 3 weeks. A subset of patients have recurrent episodes. The rash
appears acutely as a well-defined macule with a “target” appearance a
red center, a surrounding area of normal-appearing skin, and a rim of erythema
that encircles the entire lesion. The peripheral rim is very well circumscribed
and demarcated from the normal skin. Over a day, the macules may turn into
edematous plaques. As time progresses, the center of the lesion becomes purple
or dusky red. There may be only one area of involvement or hundreds in severe
cases. Erythema multiforme minor affects the palms and soles; the target
lesions in these areas can be very prominent and classic in appearance. The
mucous membranes of the oral mucosa are involved in 20% of cases of erythema
multiforme minor. Edematous pink-red plaques can be seen, as well as the more
classic target lesions. If other mucous membranes are involved, the
classification of erythema multiforme minor should not be used; the patient
more likely has erythema multiforme major.
Most cases of erythema multiforme
minor self-resolve, but they do have a tendency to recur.
Erythema multiforme major has been
considered by many to be the same entity as SJS. This may be true, because the
pathogenesis and clinical appearance can be similar. However, subtle
differences exist and warrant classifying this condition independently. Both
erythema multiforme major and SJS are most often induced by medications. The
mucocutaneous surfaces are affected to a significant degree. In severe cases, the
mucosal membranes of the respiratory and gastrointestinal tract may also be
affected. Erythema multiforme major and SJS typically begin with a nonspecific
prodrome of fever and malaise. Fever is the most frequent nonmucocutaneous
symptom. The rash begins insidiously as pink macules that quickly develop a
dusky purple central region. The typical target-like lesion of erythema
multiforme minor is usually absent in SJS but may be seen in
erythema multiforme major. Erythema multiforme major is differentiated from
erythema multiforme minor in that it affects a larger surface area and affects
two mucous membranes.
In SJS, the dusky center of the
lesion soon begins to blister, first as small vesicles and then coalescing into
larger bullae. The extent and body surface area (BSA) of blistering is used to
differentiate SJS from toxic epi- dermal necrolysis. Most authors consider
blistering of 10% of the BSA and involvement of at least two mucosal surfaces
to be definitive for SJS. Those cases with 10% to 30% BSA involvement have been
termed SJS–toxic epidermal necrolysis overlap. Cases with greater than
30% BSA involvement are considered to represent toxic epidermal necrolysis.
Light lateral pressure at the edge of a bulla or vesicle is an objective
physical test that can be performed at the bedside. Spreading or an increase in
size of the blister with pressure indicates separation of the epidermis from
the underlying dermis and is termed Nikolsky sign.
Pathogenesis: Erythema multiforme major/SJS is believed
to be a hypersensitivity reaction to certain medications. The insulting
medication is thought to be metabolized into a recognizable antigen or to act
as an antigen without metabolic degradation. Antibodies bind to the drug
antigen and form antigen-antibody complexes that can deposit in the skin and
other regions, causing an inflammatory cascade and the clinical findings.
Histology: The classic histological picture of erythema
multiforme minor and major shows an acute inflammatory infiltrate along the
dermal-epidermal junction. The stratum corneum is normal. There is an interface
dermatitis with vacuolar degeneration of the basal cell layer. The interface
dermatitis leads to necro- sis and death of the basilar keratinocytes. If the
necrosis spreads and coalesces, small areas of subepidermal blister formation
may be seen. Erythema multiforme minor can share some features with fixed drug
eruptions. In fixed drug eruptions melanophages are typically present, whereas
this is not the case in erythema multiforme. Biopsy specimens of SJS and toxic
epidermal necrolysis show more interface damage and blistering of the skin. The
plane of separation is in the subepidermal space.
Treatment: Therapy for erythema multiforme minor and
erythema multiforme major requires supportive care. The skin lesions typically
self-resolve with minimal to no sequelae. Topical corticosteroids may help
decrease the time to healing and decrease symptoms of pruritus. Recurrent
episodes of erythema multiforme due to herpesvirus infection can be treated
with chronic daily use of an antiviral agent such as acyclovir. This decreases the
recurrence of herpes simplex infection and the resulting erythema multiforme
reaction. Oral lesions can be treated with topical analgesics; the use of oral
steroids is reserved for severe cases.
SJS can be a life-threatening
condition and can progress to toxic epidermal necrolysis. For both SJS and
toxic epidermal necrolysis, the cause of the reaction should be identified and
withdrawn, and infections should be treated appropriately. These patients
require aggressive supportive care, including wound care and fluid
and electrolyte balancing. Most patients with severe involvement will benefit
from the experience of a burn unit. SJS and toxic epidermal necrolysis can be
treated similarly to burns, because the same technical issues are involved.
There is no consensus on how to treat these two conditions with medications.
The use of oral steroids early in the course of disease may help lessen the
overall involvement, but steroids increase the risk of secondary infection and
should not be used in patients with infection-induced disease. If
used late in the course of disease, they appear not to help and only increase
risk of side effects. Intravenous immunoglobulin (IVIG) has been used to treat
these conditions with varying success. If used early, it may modify the disease
course; if used late, it is unlikely to be of any help. The amount of BSA
involved with blistering is related to the prognosis. Those with greater BSA
blistering tend to fare worse than those with smaller BSA involvement.
