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.