Erythema multiforme

Definitions & Key takeaways

Erythema multiforme is an immune-mediated skin condition that typically causes red, itchy patches on the skin. It can also affect the mucous membranes of the mouth and genitals; in some cases, the patches can blister and form lesions. Erythema multiforme is commonly triggered by a Mycoplasma or Herpes simplex virus infection. Some drugs can also cause it, such as penicillins, ciprofloxacin, and anticonvulsants such as carbamazepine.

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Introduction0:00–0:14

Erythema multiforme is an acute, immune-mediated condition that affects skin and mucous membranes such as the mouth and genitals.

Skin & Mucosa0:14–1:56

The skin is the largest organ in our body, and it’s divided into three layers - the epidermis, dermis, and hypodermis. The epidermis forms the thin outermost layer of skin.
Underneath, is the thicker dermis layer. And finally, there’s the hypodermis, the deepest layer.
The epidermis itself is made of multiple layers of developing keratinocytes - which are flat pancake-shaped cells that are named for the keratin protein that they make.
Keratinocytes start their life at the lowest layer of the epidermis called the stratum basale, or basal layer, which is made of a single layer of stem cells called basal cells that continually divide and produce new keratinocytes.
These new keratinocytes then migrate upwards to form the other layers of the epidermis, such as the spinous and granular cell layers.
Below the epidermis is the basement membrane which is a thin layer of delicate tissue containing collagen, laminins, and other proteins.
Basal cells are attached to the basement membrane, and help form the dermoepidermal junction. Similar to how the skin lines the outside of the body, mucosa lines the inside of the body.
And it’s named for the surface it covers. So there’s oral mucosa, nasal mucosa, bronchial mucosa, gastric mucosa, and so forth.
Mucosa is made up of one or more layers of epithelial cells that sits on top of a layer of connective tissue called lamina propria.
Just like with the skin, there is a basement membrane that sits between and attaches the epithelial layer and the lamina propria.
Now, basal epithelial cells, as well as most cells in the body, have a protein called major histocompatibility complex or MHC class I molecule on the surface of their membrane.

Pathophysiology1:56–3:04

This protein presents peptides from within the cell to immune cells called cytotoxic T cells. If a cytotoxic T cell recognises the peptides as foreign, for example like in a virally infected cell, then the cytotoxic T cell will kill the presenting cell.
Otherwise, if the cell is healthy and the cytotoxic T cell doesn’t recognize the peptide as foreign, nothing happens. Erythema multiforme is a type IV hypersensitivity reaction, meaning that the damage is caused when cytotoxic T cells inappropriately attack the basal epithelial cells.
As part of the attack, the cytotoxic T cells release proinflammatory cytokines like interferon gamma and tumor necrosis factor alpha which attracts other immune cells to the area, causing more damage.
And the result of all of this damage is the formation of vesicles and erosions in the skin and mucosa. As the name suggests, erythema multiforme can appear in a variety of shapes and sizes.

Clinical Manifestations3:04–4:08

There can be macules, which are flat red, or pink patches. There can be vesicles which are small, raised, fluid-filled lesions or bullae which are large, raised, fluid-filled lesions.
There can also be papules which are solid elevations containing no fluid. However, the most characteristic of all erythema multiforme lesions are targetoid lesions which are between 2mm and 2 cm, and have central necrosis of the epidermis, surrounded by concentric rings of erythema, making them look like a bull’s eye or target.
Histologically, early on, there are a few lymphocytes near the dermoepidermal junction. Over time more inflammatory cells come to the area and are seen around blood vessels, basal epithelial cells start undergoing necrosis and subepithelial and intraepithelial vesicles start to appear.

Erythema Multiforme Minor4:08–5:04

For a long time, it was believed that erythema multiforme was part of a spectrum starting with erythema minor on one end, and going to erythema major to Stevens-Johnson syndrome, and the most severe of all was the toxic epidermal necrolysis or Lyell disease.
However, Stevens-Johnson and Toxic Epidermal Necrolysis are now considered totally separate diseases and erythema multiforme now encompasses only erythema multiforme minor and major.
So, let’s take a look at the differences between these two disorders. Erythema multiforme minor is a milder, condition that’s almost always triggered by a preceding infection.
It causes targetoid lesions to form on the palms and soles and the lesions are symmetric and typically spread towards the trunk.
There is typically no, or only mild, mucosal involvement in erythema multiforme minor. In erythema multiforme major two or more mucosal sites are involved, typically the oral mucosa and ocular or genital mucosa, and there are widespread skin lesions.

Erythema Multiforme Major5:04–5:53

So erythema multiforme major is more severe but is still only rarely life threatening. The lesions in the oral mucosa are usually red patches that evolve into epithelial necrosis leaving behind irregular, painful ulcerations that can bleed.
These ulcers can occur anywhere in the oral mucosa, but most often involve the labial mucosa, buccal mucosa, tongue, floor of the mouth, and soft palate.
It is very characteristic of oral erythema multiforme to cause hemorrhagic crusting of the vermilion zones of the lips. Erythema multiforme is most commonly associated with a preceding Mycoplasma or Herpes simplex virus infection.

Causes5:53–6:51

Some patients can have recurrent episodes of erythema multiforme, especially in the oral mucosa, due to Herpes Simplex virus type I or less commonly type 2.
It’s thought that the HSV proteins are similar to proteins found in the oral mucosa, causing the T-cells to get confused and attack keratinocytes expressing those proteins.
Erythema multiforme can also be caused by medications, including penicillins, sulfonamides, ciprofloxacin, and anticonvulsants such as phenytoin and carbamazepine.
In comparison to erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis are almost always due to a drug reaction, involve much more of the skin and mucosa, and are much more life-threatening.

Diagnosis & Treatment6:51–7:44

The diagnosis of erythema multiforme is based on the classic skin rash with a targetoid appearance along with the hemorrhagic crusting of the lips.
The involvement of the oral mucosa makes it hard for a person to eat and drink - leading to dehydration. So, part of treatment is maintaining good hydration which may include IV rehydration as well as pain control.
If there is an underlying cause it should be dealt with - for example, an infection should be treated and an offending medication should be stopped.
Systemic corticosteroids can be used to help reduce inflammation. The good news is that the process generally self-resolves over weeks.
In cases of recurrent bouts of erythema multiforme due to herpes simplex virus, continuous oral acyclovir or valacyclovir can be used for prevention.
Alright, as a quick recap erythema multiforme is a derangement of the immune cells that start attacking epithelial cells and that is usually triggered by an infection like Herpes simplex virus or medications.

Review7:44–8:22

Erythema multiforme minor affects only a limited region of the skin and one type of mucosa, usually the oral mucosa. Erythema multiforme major causes widespread skin lesions and affects two or more mucosal sites.
Both types can cause a skin rash that characteristically may have a targetoid appearance and bleeding, crusted lips, and should be treated with systemic corticosteroids and elimination of the triggering factor.