Introduction

Rashes are irritating but common, and most of the time it is not something to be worried about. On occasion, a rash signifies a more serious underlying condition that requires immediate medical care. What happens when rashes associated with different disorders look similar and can be easily confused? This is the case with erythema multiforme (EM) and Stevens-Johnson syndrome (SJS). 

Both conditions have similar causes and initial skin manifestations, making early diagnosis difficult.¹ EM is self-limiting and non-urgent; however, SJS is a medical emergency that can lead to mortality.¹ Hence, understanding how to identify characteristics of these conditions early is important to improve patient outcomes and limit the damage caused.

What is erythema multiforme?

Erythema multiforme (EM) is a non-life-threatening skin reaction that usually appears after an infection, most commonly caused by the herpes simplex virus (the same one that causes cold sores).³ Other triggers include Mycoplasma pneumoniae (a bacterium that causes a type of lung infection), certain antibiotics, NSAIDs (non-steroidal anti-inflammatory drugs), and some autoimmune diseases.⁴

The presentation of EM can be alarming, with target lesions like a bull’s-eye. It has a dark red centre, followed by a pale ring and then a red outer ring.³ The lesions or spots appear on the extremities, such as the hands, arms, feet, or legs, and in more serious cases, the eyes or mouth.³ It also appears symmetrically on both sides of the body, but in most cases, there are no other accompanying symptoms, although some people may feel a little tired or have a mild headache/fever.³ 

Typically, the skin reaction is self-limiting, meaning that it will resolve completely on its own without intervention or long-term complications.² The lesions can last within 1-3 weeks but can recur, especially if the underlying cause remains untreated or returns.³

The severity of the reaction is classified into EM minor and EM major. EM minor is less severe, with little to no mucous membrane (lips, mouth) involvement, while EM major has more involvement of the mucous membranes and is generally more severe.³ Both cases experience itching, burning sensations, and mild pain, which can feel worse when there are mucous membrane lesions, like in EM major.³

What is Stevens-Johnson syndrome?

Stevens-Johnson syndrome (SJS) is a rare but severe reaction that is often triggered by medications.⁵ A reaction is commonly in response to medications, such as some anti-seizure drugs (like carbamazepine or phenytoin), NSAIDs (painkillers like ibuprofen or naproxen), and sulfa-antibiotics, although, in some cases, it can be triggered by infections.^5,6

SJS often starts with flu-like symptoms such as fever, sore throat, cough, body aches, or itchy burning eyes.⁶ This is followed by widespread rashes that quickly worsen within a few days. The reaction causes mucous membranes and the skin to become inflamed and begin to peel away, similar to a severe burn.^5,7 The rashes have flat discoloured areas called macules, areas with bleeding into the skin (purpuric patches), blisters, and peeling of the skin.⁶ They heavily affect mucous membranes like the mouth, eyes, or genital areas and are usually painful.⁶

Skin detachment is an important factor to consider in SJS because, if a large portion of skin is involved, it can fall into the territory of toxic epidermal necrolysis (TEN), which can be life-threatening.⁷ Due to the extent of the damage caused, there is a risk of dehydration, infection, damage to internal organs, and even death.⁶ Treatment of SJS requires hospitalisation for management of symptoms and discontinuation of the causative medication.⁶

Similarities between EM and SJS

EM and SJS have been difficult to distinguish due to their similarities, with doctors believing that they were part of the same disease spectrum. However, they are now known to be distinct.⁸ One of the similarities is the appearance of a rash; both conditions present with red rashes and sometimes mild fever.^3,6 In severe cases of EM and in nearly all cases of SJS, the rashes can affect the mucous membranes of the mouth and eyes.^3,6 

Another similarity is that both conditions, despite their different triggers, involve the immune system reacting abnormally. These reactions appear quickly, often within days of the initial trigger.^3,7 Both conditions are so similar, especially in the early stages, that a detailed history and skin biopsy would be needed to distinguish them.

Differences between EM and SJS

Despite their similarities, it is crucial to know their differences in order to distinguish and manage them appropriately. These differences are:

Main trigger

The main trigger of EM is viral infection, usually the herpes simplex virus (HSV), though it is not just limited to this.⁴ On the other hand, medications are the main cause of SJS, with medications like antibiotics and anti-seizure medications being common triggers.⁴ 

Rash type

The rash found in EM can be described as a bull's-eye appearance with a dark red centre, followed by a pale ring and a red ring.³ In contrast, the rash found in SJS is a flat red spot that worsens and blisters, and eventually leads to peeling of the skin.⁶

Mucosal involvement

EM usually appears in the hands, arms, or feet and rarely has mild involvement of the mucosal membranes (mouth, eyes, genitals).⁹ However, SJS usually appears on the face, chest, or whole body and commonly involves severe reactions in the mucosal membranes.⁹

Severity

EM is usually mild and resolves on its own within 1-3 weeks, whereas SJS is a medical emergency that requires hospitalisation in intensive care units and has a high risk of further complications.^3,6

Systemic symptoms

Patients with EM often feel well aside from rashes, they don’t have systemic symptoms. While SJS patients usually feel very ill with fever or sore throat.¹

Diagnosis

Diagnosing EM and SJS usually starts with a well-documented history. A history of herpes outbreak is a big clue for EM, while a history of recent medication use is a flag for SJS.¹ Recognising the rash is also essential for the diagnosis. 

In unclear cases, a skin biopsy is taken; SJS shows a destruction of the entire epidermis (upper layer of skin), while EM shows inflammation of the upper skin layers.⁴ Laboratory tests are also used in the diagnosis, with a positive HSV PCR (Herpes simplex virus polymerase chain reaction) in EM, while in SJS, CBC, liver function, and renal markers are measured.⁷

Treatment

Treatments for EM and SJS are different, in that EM often does not require treatment, while SJS requires hospital care.¹ Supportive care and reassurance are the backbone for EM treatment, with antiviral therapy (acyclovir) given in recurrent cases or in active HSV-associated cases.¹⁰ 

SJS, on the other hand, requires an immediate stoppage of the causative medication, which is then followed up by admittance into specialist wards like the ICU or burns unit.¹⁰ It is important to provide monitoring and supportive treatments such as wound care, fluid replacement, or even nutritional support. Some doctors prescribe intravenous immunoglobulins (IVIG) or cyclosporine to control and limit the progression of the condition and reduce skin damage. In the hospital, the SCORETEN score is used to predict mortality in SJS cases.⁶

When to seek medical help

Although, EM is self-limiting and self-resolving, you may still wish to seek medical assistance upon discovering tell-tale signs of EM rashes. Whereas catching SJS early can make a massive difference in damage, survival, and recovery. However, not every rash is dangerous or a medical emergency. Some signs and symptoms that you should contact your doctor about are:

• A quickly spreading rash
• Painful blisters that appear in mucosal membranes (the mouth, eyes, or genitals)
• If you have a fever or flu-like symptoms that precede or overlap with a rash
• Any rash or blister you notice after starting a new drug

Summary

Erythema multiforme (EM) and Stevens-Johnson syndrome (SJS) are different skin conditions that share similar initial symptoms, and it is important to be able to distinguish between them. Usually, EM is a mild reaction to infections, mainly HSV, but it can also be caused by medications. It presents with a characteristic bull’s-eye appearance. 

SJS, on the other hand, is a medical emergency caused by a severe reaction to medications like anti-seizure medications, but can also be caused by infections. It has the characteristic traits of widespread painful rashes and peeling skin, which often requires hospitalisation. Despite their similarities, they have distinct triggers, severity, and treatments. Therefore, knowing the signs of each and acting quickly could be the difference between a short recovery or reassurance and a life-threatening rush to the hospital. You should visit your doctor once you notice signs of SJS, as this could save your life.