Introduction

Erythema multiforme (EM) is a condition that affects the skin and mucosal surfaces. It is characterised by an abnormal immune response and heightened sensitivity, leading to the appearance of ‘target’ lesions on the skin, such as the hands and feet, as well as mucosal lesions in the mouth or genital area.¹ The lesions typically occur at a single site and resolve within 7 to 21 days.¹ EM can occur following an infection, commonly the herpes simplex virus, or as an adverse reaction to a drug, most often the nonsteroidal anti-inflammatory drugs (NSAIDs).¹ It is mainly considered a result of an extreme immune response to external antigens.¹ Even though EM can occur at any age, it primarily affects young adults and its severe cases can be life-threatening. The current treatment options target symptom management, such as pain relief, but do not address the underlying causes of the disease.¹ Therefore, it is essential to understand and identify the underlying genetic factors and environmental risk factors that trigger the onset of this disease and increase its severity in different individuals. This article will describe the genetic predispositions to EM, with critical environmental factors that trigger it in individuals. This article will also touch upon the clinical symptoms of EM to provide a concise summary of its causes and effects. 

Genetic risk factors 

There can be a combination of causes of EM, ranging from infections and underlying genetic and autoimmune conditions to the administration of certain drugs. Even though the most common causes are infections, particularly infection by the herpes simplex virus (HSV), genetic factors can also play an important role.¹

The development of this disease involves a series of reactions mediated by the immune system, such as the T-cell-mediated immune response to the HSV-2 infection.² Therefore, certain genetic elements that affect components of the immune system, and thus the immune response, can create a genetic predisposition in the individual to EM. For instance, specific phenotypes of the human leukocyte antigen (HLA) can increase the likelihood that an individual will develop EM in response to stimuli.² The role of HLA class I and II molecules is to bind peptide antigens and present them to antigen-specific T lymphocytes, so that they can be recognised by CD8+ or CD4+ T cells, thereby triggering the immune response.³ 

Thus, specific HLA class alleles can be risk factors for EM by creating a genetic predisposition to antigen presentation and T-cell-mediated immune responses.² This makes some individuals have a higher chance of developing EM in response to certain infections and as part of adverse reactions to drugs.² Importantly, a study examining the relationship between HLA class II alleles and the risk of developing EM has established that the HLA DQB1*0301 allele had the strongest association with the occurrence of EM in individuals, where its presence was a high-risk factor.⁴ Furthermore, the association between HLA DQB1*0301 and EM was stronger in individuals with HSV-associated EM, highlighting the importance of the T-cell-mediated immune response in HSV-associated EM.⁴ Moreover, HLA-B35, HLA-B62n and HLA-DR53 alleles have been reported as genetic risk factors for recurrent EM, in which an individual has repeated episodes of EM over time.⁵ Overall, these findings emphasise the importance of genetic risk factors in influencing the onset and severity of developing EM in different people. 

Environmental risk factors 

The environmental factors that trigger EM can be multicombinatorial, but most importantly, viral and bacterial infections have been found to cause EM. It was reported that around 90% of EM are caused by infections, including viral infections such as HSV, adenovirus, hepatitis A, B and C, as well as measles and influenza.¹ Bacterial infections were also cited as causes, such as Mycoplasma pneumoniae, Staphylococcus, salmonellosis, and tuberculosis, among others.¹ Furthermore, autoimmune conditions were also reported to have a relationship with the risk of developing EM, including systemic lupus and Raynaud's syndrome. Also, certain vaccinations have been identified as causing EM, such as vaccinations for Bacille Calmette-Guerin, tetanus and polio.¹ Along with this, some of the drugs which can cause adverse events triggering EM were reported to include antibiotics, antituberculosis medications and antipyretics.¹

Aside from these, other environmental triggers for EM could include exposure to ultraviolet radiation and sunlight, which can trigger the activation of HSV-associated EM ². Radiation therapy was also reported to be a cause, along with physical trauma (known as the Koebner phenomenon), where lesions can occur on areas that have been injured. Acute alcoholism was also reported to be a stimulating factor for HSV-associated EM. The underlying immune conditions that can trigger EM include lupus erythematosus, dermatomyositis, inflammatory bowel disease, and renal carcinoma, which can either increase the risk of EM or be associated conditions.²

Moreover, EM can be caused by chemicals such as those inside electronic cigarettes or vapes.⁶ The components in these devices, particularly propylene glycol and nicotine, were reported to induce exaggerated immune responses in individuals with EM-like characteristics. It was reported that electronic cigarettes can lead to oral EM, where ulcers and lesions on the lips can occur, causing pain while eating and drinking. This is due to the damaging effects of these chemicals on the oral mucosa, which serves as a protective layer against pathogens.⁶

Clinical symptoms of erythema multiforme

EM can be classified by its minor and major forms based on the extent and severity of skin and mucosal involvement.¹

Early/Nonspecific Symptoms:

• EM minor: usually not present, possibly fatigue or mild respiratory effects. These nonspecific symptoms are usually present before 3 days of lesion development
• EM major: systemic symptoms including fever, aches, cough and chest pain. These nonspecific symptoms are usually present before 2 weeks of lesion development

Cutaneous Features: 

• Target lesions are present and show three concentric zones with outer, middle and central erythematous rings. Lesions can be up to 3 cm in size

Mucosal Features:

• These lesions can be common in the mouth and genital areas, where they can start as blisters and develop into ulcers. 
• It can lead to pain and difficulty associated with eating and drinking

Location of Lesions:

• EM minor: lesions typically occur on extremities, and lesions on mucosal areas are rare
• EM major: lesions are present in a wider range of areas with greater skin and mucosal involvement

Prognosis:

• EM minor: Lesions can resolve in 2 to 3 weeks with no scars present
• EM major: lesions can resolve in 4 to 6 weeks, and severe cases can be life-threatening¹

Summary

Erytherma multiforme (EM) is a skin condition that is caused by a misregulated immune response that leads to the development of lesions in the skin and mucosal surfaces. Its causes can be multifactorial, spanning from genetic to environmental risk factors. Bacterial and viral infections, especially herpes simplex virus, are the leading causes of EM, along with autoimmune diseases and genetic predispositions, particularly the presence of specific alleles of the human leukocyte antigen gene, which increase the probability of developing EM. Along with this, other environmental risk factors for EM could be exposure to ultraviolet radiation, the use of electronic cigarettes, and radiation therapy. The accurate causes and the interplay of genetic and environmental risk factors of EM are important to properly diagnose and treat this disease.