Introduction

Erythema multiforme (EM) is a sudden, short-term inflammatory condition that usually resolves on its own. It affects both the skin and the soft mucosal linings of the body, like the mouth or eyes. EM shows up as rashes in various forms, often in circular shapes with three concentric zones called target lesions.¹ It occurs because the immune system reacts strongly against a perceived threat. While most EM episodes (approximately 90% of cases) are caused by a viral infection (herpes simplex virus), medications can also induce this condition, leading to what is known as drug-induced erythema multiforme (DIEM).^1,2

Hypersensitivity reactions: understanding EM minor vs EM major

Erythema multiforme is classified into erythema multiforme minor and erythema multiforme major based on mucosal involvement.

Erythema multiforme minor

EM minor usually occurs when the immune system overreacts to a trigger and produces special proteins called antibodies. These antibodies stick to foreign particles called antigens, forming tiny complexes. Later, these antigen-antibody complexes circulate in the blood and can get stuck in blood vessels, leading to redness and swelling. This whole process is seen with a type III hypersensitivity reaction. Symptoms such as fever, itchy skin, and joint pain may develop in response to these clumps.³

Erythema multiforme major

EM major appears when the body’s immune system mistakenly attacks its own tissues, a process referred to as an autoimmune response. It can also develop if erythema multiforme minor is not treated. Microscopic examination of skin tissue may reveal the presence of specific antibodies produced by the body that attack certain proteins in the skin (desmoplakins 1 and 2), confirming the involvement of the immune system in causing EM major.³

Signs and symptoms

Drug-induced erythema multiforme (DIEM) looks very similar to other types of EM. It results in the formation of different kinds of skin lesions and rashes that often follow a pattern wherever they appear on the body. 

• Polymorphic Eruption:

 The term 'multiforme' indicates the appearance of skin outbreaks in diverse forms such as flat spots (macules), small bumps (papules), tiny blisters (vesicles), or even open sores (ulcers).²

• Target Lesions:

 The most identifiable sign of DIEM presents as a bull’s-eye or a target with rings. A typical target lesion has three rings circling a darker center, while an atypical one has only two rings.²

• Acral distribution: 

A key feature of DIEM is the development of target lesions on the extremities, such as the arms and legs.²

• Mucosal involvement: 

In DIEM, the oral mucosa is most commonly involved, particularly in areas such as the lips, tongue, and inner lining of the cheeks (buccal mucosa).²

Mechanism behind drug-induced erythema multiforme

Altered drug metabolism

The mechanism begins with an unusual breakdown of drugs, producing harmful byproducts, through a process called the cytochrome P450 pathway. These toxic substances can induce the skin reactions seen in EM.²

Immune cell infiltration and cytokine release

In the initial stages of EM, certain immune cells (macrophages and CD8 T lymphocytes) enter the skin and release special proteins (cytokines) that cause inflammation, leading to the death of skin cells.⁴

Keratinocyte apoptosis

Skin damage in erythema multiforme arises because skin cells are programmed to die in a controlled manner, called apoptosis. This process starts with the binding of special molecules (Fas ligand) present on activated immune cells to Fas receptors present on keratinocytes. This interaction releases proteins (caspases) that tell the skin cells to self-destruct. The resulting cell death can affect small areas or even larger patches of skin in people with EM.² 

Role of tumour necrosis factor-alpha (TNF-α) in DIEM

One notable difference in drug-induced erythema multiforme (DIEM) is the involvement of a protein called tumour necrosis factor-alpha (TNF-α) instead of another protein called interferon-gamma in causing skin cell damage. TNF-α plays a key role in triggering the death of skin cells.⁴

Genetic susceptibility

People with certain types of human leukocyte antigen (HLA) genes are more likely to develop recurrent EM. These genes can influence the immune response in causing this erythema multiforme by recognising foreign and body particles.⁴ 

Common offending medications

Various classes of medications are known to cause DIEM. These medicines or their breakdown products can induce a specific immune response in people who are more sensitive, leading to the destruction of skin cells.²

Antibiotics

• Sulfonamides are the most common triggers, accounting for about 30% of DIEM. One example from this class of medication is the combination drug named trimethoprim-sulfamethoxazole (cotrimoxazole or bactrim)
• Tetracycline antibiotics (doxycycline and minocycline) are also known to cause EM, sometimes associated with a photosensitivity reaction upon exposure to sunlight. People with a slow acetylator genetic type process certain medicines more slowly, which increases their risk of side effects from these drugs^1,3
• Other antibiotics that may cause erythema multiforme (EM) include penicillins (ampicillin, amoxicillin), cephalosporins (cefotaxime, cefixime, cefaclor, cephalexin), fluoroquinolones (ciprofloxacin), macrolides (erythromycin), and glycopeptides (vancomycin)^2,3

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs, which are widely used for relief of pain, fever, and inflammation, such as piroxicam, fenbufen, ibuprofen, ketoprofen, naproxen, tenoxicam, diclofenac, sulindac, aspirin, phenylbutazone, oxyphenbutazone, and phenazone, are known to cause DIEM.^2,3

Anticonvulsants

These drugs are commonly used to control epileptic seizures and include barbiturates, carbamazepine, hydantoin, phenytoin and valproic acid. The body changes these medicines into reactive substances (metabolites), which may act like “haptens” and bind to proteins, making them appear as targets for the immune system to attack.³ 

Other medications

• Allopurinol, a drug used in the management of gout, has been linked with erythema multiforme (EM)³
• Anti-tuberculoid drugs, such as rifampicin, ethambutol, isoniazid and pyrazinamide, are also associated with EM^3,4
• Antifungals, including fluconazole, nystatin, and griseofulvin, have been reported to cause EM³
• Anti-depressants, such as lamotrigine and sertraline, can also produce EM³
• Oral hypoglycaemic agents like chlorpropamide and tolbutamide have also been listed as possible triggers.³
• Chemotherapeutic drugs, including 5-fluorouracil (5-FU), and actinomycin D, including methotrexate (which is particularly linked to oral EM), are also inducers of EM^5,6
• Antipyretics such as acetaminophen (paracetamol) is also a potential trigger⁵
• HIV treatment medications have been found to have either a direct or indirect role in the development of EM⁴

Diagnosis: clinical and laboratory approach

• Temporal relationship: 

The occurrence of signs and symptoms after the patient has started taking a particular medication suggests drug-induced erythema multiforme (DIEM).² For example, an individual may develop a target-like body rash after 15 days of taking ibuprofen regularly.⁷

• Clinical examination: 

A detailed clinical examination helps identify the rash, its distribution, and whether mucosal involvement is present.²

• Exclusion of other causes: 

If the temporal relationship with drug intake is not strong, it is essential to rule out infections (especially Herpes simplex virus or HSV).²

• Biopsy: 

A sample of a target-like rash may be taken and examined under a microscope.⁷ Swelling between skin cells and death of keratinocytes can be observed. These changes lead to the formation of tiny blisters inside or under the skin. Clusters of immune cells are also often seen around blood vessels in the top layer of the skin.⁸

• Drug testing (with caution): 

This may be performed to check if a medicine caused the reaction. However, such tests are usually avoided if the drug is not considered essential, as they may trigger a serious skin reaction. For example, tests were not conducted for medicines like silver sulfadiazine and doxycycline because of this risk.¹ 

• Other laboratory tests: 

A complete blood count (CBC) may show unusual results, such as a drop in all types of blood cells, which has been noticed in ibuprofen-related cases. Tests for infections (HIV, hepatitis) and for certain autoantibodies (ANA) may also be conducted to rule out alternative causes.⁷

Management and treatment strategies

The primary step in managing suspected drug-induced erythema multiforme (DIEM) is the immediate identification and discontinuation of the causative drug.^2,9 This prevents the immune reaction from worsening. Furthermore, it is also essential to avoid reusing the same drug or other chemically related drugs, as they may trigger a similar reaction. Additionally, the treatment measures should be tailored to the extent and severity of the patient’s symptoms, with special attention to mucosal membrane involvement.⁹

Mild cases (EM minor)

• Supportive care: Mostly mild cases are managed with general supportive measures such as skin care, hydration, and rest²
• Topical corticosteroids: Steroids in the form of cream or ointment may be applied to reduce mild inflammation and discomfort²
• Oral antihistamines: Recommended for symptomatic relief, especially for itching²
• Antiseptics: Antiseptic mouthwashes (e.g., betadine) are useful when, there is mild involvement of mucosa²

Moderate cases (with mucosal and/or ocular involvement)

• Systemic Steroids: oral corticosteroids such as methylprednisolone or prednisolone are commonly prescribed. The starting dose of methylprednisolone is usually around 20 mg per day, and later be adjusted up to a maximum of 60 mg per day if needed. Prednisolone 40 mg is sometimes used when the mouth or eyes are involved. It is recommended to gradually decrease the dose over two to four weeks rather than stopping suddenly²
• Antihistamines and antiseptics: These remain part of the regimen to provide symptomatic relief and lower secondary infection risks²
• Ophthalmic Consultation: Patients with eye (ocular) involvement must consult an ophthalmologist. Eye drops with steroids like betamethasone or combination drops containing both antibiotics and corticosteroids may be prescribed to protect the eyes and prevent long-term complications²

Severe cases

1. Hospitalisation: Required in case of severity, especially when mouth sores make it hard to eat or drink. Hospital care helps manage pain, provide intravenous fluids, ensure nutrition, and prevent complications until symptoms improve²
2. Electrolyte repletion: Severe cases often need correction of electrolyte imbalances caused by poor intake or fluid loss²
3. Intravenous steroids: IV steroids may be used to control inflammation and promote skin healing in extensive or rapidly progressing cases²

Cases non-responsive to steroids (resistant cases)

People who do not respond to initial steroid therapy may require other immunosuppressive or immunomodulatory agents such as dapsone, cyclophosphamide, azathioprine, levamisole, cyclosporine, thalidomide, interferon-α, apremilast, mycophenolate mofetil, adalimumab, hydroxychloroquine.²

Summary

Erythema multiforme (EM) is a short-term skin reaction that can sometimes affect soft tissues like the mouth or eyes. The key feature is target-shaped lesions, round spots with three rings around a darker centre. Out of all the EM cases, about 10% of EM cases are due to medicines. The body sometimes processes these medicines in a way that produces harmful byproducts through the cytochrome P450 pathway. These byproducts trigger an excessive immune response. A protein called tumour necrosis factor alpha (TNF-α) helps destroy skin cells, causing the rash.
Several classes of medications are known to cause this reaction, including antibiotics, anticonvulsants, non-steroidal anti-inflammatory drugs (NSAIDs), allopurinol, tuberculosis drugs, antifungals and others. 

The most critical step in treating drug-induced erythema multiforme is to stop the suspected drug immediately. It is also crucial to avoid taking the same medicine again or any medication with a similar chemical structure unless a doctor confirms it as safe in order to prevent the reaction from recurring or worsening. 

EM can be mistaken for more serious conditions like Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), but EM is now recognised as a separate condition because it has different causes, signs, mechanisms, treatments and outcomes. Treatment is personalised based on the severity of symptoms and whether mucous membranes like the mouth or eyes are involved.