Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe life-threatening conditions with morality rate of ≈5% and ≈30% correspondingly. They belong to a group of so-called dermatologic emergencies which also encompasses such horrifying maladies like cutaneous anthrax, necrotizing fasciitis, meningococcemia, staphylococcal scalded skin syndrome, etc.
Both SJS and TEN, as well
erythema multiforme (EM) per se, represent a cluster of skin diseases known as interface dermatitides with characteristic damage of dermal-epidermal junction and formation of subepidermal blisters. For years dermatologists regarded SJS and TEN as severe variants of erythema multiforme. It sounds quite reasonable because despite of certain difference in etiology and presentation, the pathogenesis of all three diseases overlaps in many aspects:
1) Hypersensitivity reaction to an exogenous antigen, either drug or infection
2) Epidermal infiltration with CD8 lymphocytes and macrophages, and dermal infiltration with CD4 lymphocytes
3) Cell-mediated cytotoxicity affecting keratinocytes
• Perforin-granzyme and/or FAS-FAS ligand mechanisms
4) Apoptosis (sometimes named as necrosis or dyskeratosis) of keratinocytes often affecting the full thickness of the epidermis
5) Vacuolization and formation of subepidermal blisters
What is the difference? What is the matter to distinguish these conditions?
The answer is simple: erythema multiforme is a benign, self-limited disorder with excellent prognosis. On the opposite side, SJS and TEN are rapidly developing and potentially fatal diseases and their prompt diagnosis and treatment can greatly improve outcome and reduce mortality rate. Below you can find a brief presentation of each of these diseases oriented mainly toward their differential diagnosis.
Erythema multiforme
1) Precipitating factors: infections (HSV, EBV, histoplasma,
Mycoplasma pneumonia, etc)
2) Skin rash characteristics: three-zone target lesions – centrally located necrotic area or vesicle, intermediate zone of edema and blanching, and peripheral hyperemia;
3) Location of skin rash: extremities are mostly affected
4) Mucosal involvement
a) Without oral cavity lesions: erythema multiforme minor
b) With oral bullae and erosions: erythema multiforme major (bullous erythema multiforme)
SJS
1) Provoking factors
a) Drugs: sulfonamides, anticonvulsants, NSAIDs, aminopenicillins, cephalosporins, etc
b) Infections: viral, bacterial, or fungal
o A history of infection alone, without medication treatment, may direct the diagnosis toward bullous EM
c) Graft-versus host disease (bone marrow transplantation)
d) Malignancies
2) Skin rash characteristics: two-zone target (targetoid) lesions – confluent erythematous macules with purpuric centers which rapidly evolve into flaccid blisters (full-thickness epidermal necrosis); later blisters rupture with denudation of red oozing dermis. Total area of detached or “detachable” epidermis with positive Nikolsky sign is less than 10% of body surface area (BSA).
3) Location of the rash: the lesions appear on the face and upper trunk and then extend to the abdomen, back and proximal extremities; distal extremities are relatively spared.
4) Mucosal involvement: erythema, blisters and erosions affecting the lips, oropharynx, conjunctiva, esophagus, trachea, bronchi, urethra, etc; hemorrhagic crusts over the lips.
TEN
Provoking factors, skin lesion characteristics and location, and mucosal involvement are the same as in SJS with only exception of the area of affected epidermis: bullous changes are seen over 30% of BSA and more.
When blistering eruptions are found over from 10 to 30% of the BSA, the condition is referred to as
SJS/TEN overlap syndrome.
Because SJS, TEN, and SJS/TEN overlap syndrome have similar precipitating factors, identical pathomorphologic features and comparable clinical patterns, they conventionally considered as different representatives of the same disease process.
Staphycoccal Scalded Skin Syndrome (SSSS) is a rare type of staphylococcal infection characterized by an extensive detachment of the epidermis, which clinically can resemble TEN. But opposite to TEN, SSSS affects predominantly neonates and infants and is associated with much lower mortality rate. This condition occurs in children with a history of staphylococcal infection and fully blown clinical presentation: focus of pyogenic inflammation, fever, positive bacterial culture, etc.
The pathogenesis of SSSS is linked to staphylococcal exotoxins, which damage desmosomes of keratinocytes in the stratum granulosum with subsequent detachment of stratum corneum. Characteristically, inflammatory infiltration and apoptosis/necrosis of keratinocytes are not seen.
Even gross appearance of the SSSS blisters is similar to that seen in SJS and TEN (flaccid bullae, positive Nikolsky sign), the diagnosis is usually made based on clinical findings and biopsy is rarely required. With prompt recognition and administration and proper antibiotics, the prognosis is good, and the lesions will heal without scarring.
Finally, I would like to explain why I wrote so long article about these relatively rare skin diseases. The first of all, there are not so many potentially fatal skin diseases and, I believe, a future physician has to be at least aware of them. The second, the dermatopathologist plays a crucial role in rapid recognition of SJS and TEN: characteristic skin biopsy findings (a combination of dyskeratosis, subepidermal blisters and sparse mononuclear infiltrate) along with macroscopic appearance of skin rash directly prompt diagnosis toward these pathologies. With early diagnosis followed by aggressive treatment the patients have great chances to recover.
