Erythema multiforme is a skin condition that appears suddenly, often triggered by an infection or medication, creating distinctive target-shaped spots that can affect not just the skin, but sometimes the mouth, eyes, and other sensitive areas of the body.
Understanding How Common Erythema Multiforme Is
Erythema multiforme is considered a rare skin condition, affecting less than 1% of the population each year. This means that out of every 100 people, fewer than one will develop this condition annually. While anyone can be affected by erythema multiforme, it shows a clear pattern in who it affects most often.[1][2]
The condition is most commonly seen in young adults, particularly those between the ages of 20 and 40 years. Children and people under 40 are also frequently affected, though the condition can appear at any age. Research shows that males are slightly more likely to develop erythema multiforme than females, though the difference is modest. There is no clear connection between erythema multiforme and race or ethnicity, meaning it can affect people of all backgrounds equally.[3][5]
Despite being rare, erythema multiforme is an important condition for healthcare providers to recognize quickly. The condition can range from mild cases that only affect the skin to more severe forms that involve mucous membranes (the moist linings of the mouth, eyes, and genitals), which can significantly impact a person’s ability to eat, drink, or see comfortably.[1]
What Causes Erythema Multiforme
The exact cause of erythema multiforme remains not fully understood, but researchers have identified that it is an immune-mediated reaction, meaning the body’s defense system responds to a trigger in a way that causes the skin changes. The condition is not something a person is born with or inherits from their parents. Instead, it develops as a reaction to specific triggers that vary from person to person.[2][5]
Infections are responsible for triggering erythema multiforme in about 90% of cases. The most common culprit is the herpes simplex virus (HSV), which is the same virus that causes cold sores. Both HSV type 1 and HSV type 2 have been shown to trigger erythema multiforme. What happens is that after a person has a herpes outbreak, their immune system continues to react, and this can lead to the development of the skin rash weeks later. The virus itself doesn’t directly cause the rash, but rather the body’s immune response to viral fragments triggers the condition.[3][5]
Another important infectious trigger is Mycoplasma pneumoniae, a type of bacteria that causes lung infections and pneumonia. This is the second most common cause of erythema multiforme, particularly in children. Other infectious agents that have been linked to the condition include Epstein-Barr virus, cytomegalovirus, influenza virus, and even certain fungal infections like vulvovaginal candidiasis. More recently, SARS-CoV-2, the virus that causes COVID-19, has also been associated with erythema multiforme.[3][5]
Medications account for less than 10% of erythema multiforme cases, but they are still an important cause to consider. The drugs most commonly associated with the condition include nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, which are often used for pain and fever. Antibiotics, particularly sulfonamides, penicillins, erythromycin, nitrofurantoin, and tetracyclines, can also trigger the condition. Other medications that have been linked to erythema multiforme include drugs used to treat seizures (antiepileptics), barbiturates, statins used for cholesterol, and certain newer medications called TNF-alpha inhibitors.[5][9]
Vaccinations have occasionally been reported to trigger erythema multiforme, though this is rare. Vaccines that have been associated with the condition include those for measles, mumps, and rubella; hepatitis B; meningococcal disease; pneumococcal disease; varicella (chickenpox); influenza; and Haemophilus influenzae. The incidence of vaccine-related erythema multiforme is very low, and in infants, vaccinations are actually the most common cause.[5][9]
In some cases, other medical conditions have been linked to erythema multiforme, particularly in people who experience persistent or recurring episodes. These include inflammatory bowel disease, hepatitis C, certain cancers including leukemia and lymphoma, and in rare cases, menstruation. However, in many cases of erythema multiforme, despite thorough investigation, the exact trigger remains unknown.[3][5]
Who Is at Higher Risk
Certain groups of people and specific circumstances can increase the likelihood of developing erythema multiforme. Understanding these risk factors can help people and their healthcare providers be more alert to the possibility of the condition developing.
People who frequently get cold sores caused by the herpes simplex virus are at increased risk. Since HSV is the most common trigger of erythema multiforme, those with recurrent herpes infections may experience multiple episodes of the skin condition. There appears to be a genetic component to this, as people who carry a specific gene variation called the HLA-DQB1*0301 allele are more susceptible to developing herpes-related erythema multiforme. Multiple other genetic variations have been associated with the recurrent form of the condition.[3][5]
Young adults and people under 40 years of age are at higher risk simply because the condition is more common in this age group. Being male also slightly increases the risk, though the difference is not dramatic. Children who develop lung infections, particularly those caused by Mycoplasma pneumoniae, are at increased risk of developing erythema multiforme as a complication of their infection.[1][5]
People taking certain medications, especially if they have just started a new drug within the past two months, are at risk. This is particularly true for those taking antibiotics, anti-seizure medications, or NSAIDs. Anyone who has had erythema multiforme in the past is at risk for recurrence, especially if the original trigger (such as herpes simplex virus) is still present or recurring.[5][13]
People with certain chronic medical conditions, such as inflammatory bowel disease or those undergoing treatment with immunotherapy drugs, may also have an elevated risk. However, it’s important to note that having one or more risk factors doesn’t mean a person will definitely develop erythema multiforme, and the condition can also occur in people with no apparent risk factors.[3][5]
Recognizing the Symptoms
The symptoms of erythema multiforme can vary considerably from person to person, ranging from mild skin changes to more severe involvement of multiple body areas. The hallmark feature is a distinctive rash that can take several forms, which is why the condition is called “multiforme,” meaning multiple forms.
The most characteristic feature is the development of target lesions, also called “bull’s-eye” lesions. These spots look like a shooting target, with three distinct rings of color. The center is typically dark red or dusky, sometimes containing a blister or crust. This is surrounded by a paler, lighter ring, and the outermost ring is red. These target lesions are the key identifying feature that helps doctors recognize erythema multiforme.[1][3]
The rash typically begins on the hands and feet, particularly on the back of the hands and tops of the feet, before spreading upward toward the trunk, chest, back, and face. The distribution is usually symmetrical, meaning it appears on both sides of the body in similar patterns. The rash commonly favors extensor surfaces, which are the outer sides of the arms and legs that stretch when you bend your joints.[3][5]
The skin lesions start as small, round, slightly raised red spots. Over the course of three to four days, these spots evolve into the characteristic target shapes. Some spots develop into raised bumps or small blisters on the skin. The rash can feel itchy, cause a burning sensation, or be painful to the touch. The skin may also become swollen in the affected areas.[1][4]
Beyond the skin, some people experience other symptoms. Feeling tired, having a headache, or experiencing general malaise (feeling unwell) can occur. Some people develop a fever before or during the outbreak. Joint pain and soreness can accompany the rash. Eye symptoms can include sensitivity to light, blurred vision, sore or red eyes, and excessive tearing.[1][4]
In the more severe form called erythema multiforme major, the mucous membranes become involved. This can cause blisters and sores inside the mouth, making eating and drinking painful. The lips may become crusted and covered with painful sores. The eyes can be affected, leading to redness, pain, and vision problems. Genital involvement can make urination painful. When these mucous membrane areas are affected, the person typically feels quite ill, with fever and significant discomfort.[1][2]
The symptoms that affect the skin typically appear suddenly, developing over 48 to 72 hours. The lesions remain in fixed locations for at least seven days, which helps distinguish erythema multiforme from other similar-looking conditions like hives, where individual spots typically disappear within 24 hours. The rash usually begins to fade after about two to four weeks, healing without leaving scars, though the skin where the spots were may look darker for several months after healing.[2][4]
Preventing Erythema Multiforme
Preventing erythema multiforme can be challenging because the condition often appears suddenly and without warning. However, there are strategies that can help reduce the risk of developing the condition or experiencing recurrent episodes, particularly when the trigger is known.
For people who experience recurrent erythema multiforme triggered by herpes simplex virus infections, preventive treatment with antiviral medications can be highly effective. Taking antiviral drugs like acyclovir, valacyclovir, or famciclovir on a continuous basis can suppress herpes virus outbreaks and thereby prevent the episodes of erythema multiforme that would otherwise follow. This approach is typically recommended for people who have five or more episodes of erythema multiforme per year. The preventive treatment may need to be continued for six months, a year, or sometimes longer, depending on how well it works and how frequently episodes occur.[5][9]
Avoiding known medication triggers is another important prevention strategy. If a person has had erythema multiforme triggered by a specific drug in the past, they should inform all their healthcare providers about this reaction. The medication should be avoided in the future, and alternative treatments should be used. When starting any new medication, people with a history of erythema multiforme should be monitored carefully, especially during the first few weeks of treatment when drug reactions are most likely to occur.[4][5]
Managing underlying infections promptly and effectively may help prevent erythema multiforme. For example, treating cold sores quickly when they appear, or seeking early treatment for respiratory infections, may reduce the likelihood of developing the skin reaction. However, even with prompt treatment of the initial infection, erythema multiforme can still develop because it is an immune response that occurs after the infection begins.[3]
People with chronic conditions that have been associated with erythema multiforme, such as inflammatory bowel disease, should work with their healthcare providers to keep these conditions well-controlled. While the link between these conditions and erythema multiforme is not always clear, good overall health management is beneficial.
It’s important to understand that erythema multiforme itself is not contagious. The rash cannot spread from one person to another. However, if the condition was triggered by an infection like herpes simplex virus or Mycoplasma pneumoniae, these infections themselves can be contagious. A person who catches one of these infections from someone else may or may not develop erythema multiforme as a result, since not everyone who gets these infections will have this particular immune response.[1][8]
How the Body Changes During Erythema Multiforme
The changes that occur in the body during erythema multiforme involve complex interactions between the immune system and the skin. Understanding these mechanisms helps explain why the condition appears the way it does and why it responds to certain treatments.
Erythema multiforme is fundamentally a hypersensitivity reaction, which is a type of overactive immune response. Specifically, it is considered a type IV hypersensitivity reaction, also called a cell-mediated immune response. This means that certain immune cells, rather than antibodies, are primarily responsible for the changes seen in the skin.[2][7]
The process begins when a trigger, most commonly herpes simplex virus, is present in the body. Research has shown that in herpes-related erythema multiforme, fragments of viral DNA are carried by certain immune cells (CD34+ cells and mononuclear cells) that have a special ability to home in on the skin. These cells transport the viral DNA fragments to the skin, depositing them in the epidermis, which is the outermost layer of skin, and specifically into cells called keratinocytes, which are the main cells that make up this layer.[3][12]
Once viral DNA fragments are present in the skin, they trigger a strong immune reaction. The immune system recognizes these viral fragments as foreign and mounts an attack. This involves the activation and recruitment of specific types of immune cells called T lymphocytes (T cells). CD8 T lymphocytes and macrophages infiltrate the epidermis, while CD4 lymphocytes accumulate in the deeper layer called the dermis.[7]
These immune cells don’t directly destroy skin cells in large numbers. Instead, they release chemical messengers called cytokines. One particularly important cytokine is interferon-gamma, which has been found in high levels in herpes-related erythema multiforme. In medication-triggered cases, different cytokines like tumor necrosis factor-alpha (TNF-alpha) have been detected. These cytokines amplify the inflammatory response and signal other immune cells to join the attack.[5][7]
The cytokines released by immune cells cause the skin cells to undergo apoptosis, which is a form of programmed cell death. This cell death is what creates the dusky, dark centers of the target lesions. The surrounding inflammation causes blood vessels in the skin to dilate and become leaky, which leads to the redness and the pale, swollen ring in the middle of the target. The outermost red ring represents the area where blood vessels are dilated but cells are less damaged.[7]
The pattern of target lesions reflects zones of varying intensity of this immune attack and cell death. The changes occur symmetrically on both sides of the body because the immune cells and viral fragments are distributed through the bloodstream. The preference for hands, feet, and extensor surfaces may relate to temperature differences in these areas or other factors that make them more susceptible to this type of immune reaction.
In erythema multiforme major, when mucous membranes are involved, similar immune processes occur in the lining tissues of the mouth, eyes, and genitals. The inflammation and cell death in these sensitive tissues cause the painful blisters, erosions, and ulcerations that characterize the more severe form of the condition.[2]
Interestingly, the immune reaction in erythema multiforme is self-limited, meaning it naturally runs its course and stops without continuing indefinitely. The lesions typically begin to heal after seven to ten days as the immune response subsides. However, in some people, particularly those with recurrent herpes infections, the cycle can repeat each time the trigger reappears, leading to recurring episodes of erythema multiforme.[2][3]
