Erythema multiforme (EM) is an immune-mediated inflammatory skin condition associated with several viral infections, that appears with red patches evolving into target lesions, typically on both hands. It is typically associated with infection by either herpes simplex virus or Mycoplasma pneumoniae.
It is a type IV hypersensitivity reaction in which T-lymphocytes target skin keratinocytes due to the presence of specific proteins that resemble antigens of HSV, Mycoplasma, or other pathogens and foreign substances. to a severe, life-threatening form known as erythema multiforme major (or erythema multiforme majus) that also involves mucous membranes.
Consensus classification:
- Erythema multiforme minor—typical targets or raised, edematous papules distributed acrally (on fingers and toes)
- Erythema multiforme major—typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes; epidermal detachment involves less than 10% of total body surface area
The mild form usually presents with mildly itchy (but itching can be very severe), pink-red blotches, symmetrically arranged and starting on the extremities. It often takes on the classical "target lesion" appearance, with a pink-red ring around a pale center. Resolution within 7–10 days is the norm.
Individuals with persistent (chronic) erythema multiforme will often have a lesion form at an injury site, e.g. a minor scratch or abrasion, within a week. Irritation or even pressure from clothing will cause the erythema sore to continue to expand along its margins for weeks or months, long after the original sore at the center heals.
Causes
Erythema multiforme typically arises as a type IV hypersensitivity reaction to certain infections or, rarely, certain medications. The most common trigger is an infection with any type of the herpes simplex virus. The second most common trigger, and the most common in children, is infection with Mycoplasma pneumoniae, most commonly as an atypical pneumonia. When the body encounters these triggers, the immune system responds by activating various cells to fight off what it perceives as harmful invaders.
The pathogenic immune response in EM involves both CD4+ helper T cells and CD8+ cytotoxic T cells, which orchestrate a type IV hypersensitivity reaction. Upon activation, these T cells release proinflammatory cytokines such as IFN-γ and TNF-α. Despite the known association with IFN-γ, erythema multiforme is not considered a humorally-mediated autoimmune reaction. In addition to the differing pathogenesis, SJS/TEN also differs in its clinical characteristics, and may be excluded based on clinical characteristics alone.
Herpes simplex virus
Herpes simplex virus (HSV) is by far the most frequent cause of erythema multiforme. HSV DNA is also detected in nearly half of patients with idiopathic EM, suggesting that the true frequency is even higher than traditionally thought.