Overview

When it comes to skincare, there is a panoply of advice and recommendations from different nutraceutical websites and skincare companies on how to care for your skin optimally. These recommendations include: using sunscreen, reducing stress and UV exposure, and applying appropriate skincare products. However, have you considered the side effects of certain medications on your skin?

Beyond minor rashes and allergies, the side effects of some medications and other factors can elicit chronic dermatological emergencies that require medical attention. Also, these conditions are associated with significant morbidity, mortality, and widespread systemic complications. In this article, we’ll take you through the differences between these skin conditions: Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome. 

What are toxic epidermal necrolysis (TEN) and stevens-johnson syndrome (SJS)?

Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson Syndrome (SJS) are rare and severe cutaneous conditions caused by hypersensitivity reactions to certain medications affecting the skin and mucous membranes.¹ In 1956, Alan Lyell, a Scottish dermatologist, described 4 patients with an eruption similar to scalding of the skin, which he called toxic epidermal necrolysis (TEN).² TEN is characterised by necrosis of the skin cells, called keratinocytes, with separation of the epidermis from the underlying dermis.² 

SJS was first described as an acute mucocutaneous syndrome in 1922. This condition is characterised by purulent conjunctivitis and stomatitis with extensive maculopapular rash.² TEN and SJS are usually caused by medications or infections that stem from cell-mediated and, commonly, drug-specific reactions that are toxic to the cells, triggering widespread dermal-epidermal detachment.³   

These conditions affect about 1-10 people per million population per annum.⁴ Short and long-term complications include visual impairment, adverse effects on mental health, and quality of life.⁴ TEN and SJS can affect individuals regardless of age. However, TEN is more common in people assigned female at birth (AFAB), while SJS is more prevalent in people assigned male at birth (AMAB). Incidence increases with age and exposure to certain risk factors, which include underlying comorbidities, genetic factors, immunosuppression, a history of allergies to medications, systemic lupus erythematosus (SLE), disorders of the connective tissues, psoriasis, epilepsy, malignancy, and diabetes mellitus.⁵ 

Causes and pathomechanism of TEN and SJS

In approximately 70% of cases, TEN is considered to be a hypersensitivity reaction to drugs. It typically occurs between 7-21 days after exposure to the implicated drug, but can be much longer.⁶ According to the European Severe Cutaneous Adverse Reaction (EuroSCAR) study, the following drugs have been classified as high-risk medications that can trigger the development of SJS and TEN. These drugs include allopurinol, carbamazepine, phenytoin, oxicam non-steroidal anti-inflammatory drugs (NSAIDs) such as piroxicam, phenobarbital, cotrimoxazole, and other sulfonamides. 

It is essential to note that not all cases of SJS and TEN are caused by drugs. Other causative factors include infection with the organism Mycoplasma pneumoniae, vaccination, hepatitis A, viral infections caused by the Herpes Simplex Virus, and Coxsackie virus.⁷ The physical factors that can trigger drug-induced SJS and TEN are exposure to ultraviolet light and X-rays.⁷

SJS and TEN are mainly drug hypersensitivity reactions in which the cytotoxic T lymphocytes play a major role in the initiation phase of these conditions. Three hypotheses about how drugs trigger an immunological response to cause SJS and TEN have been described.^8,9 These are:

• Hapten/pro-hapten concept: This states that small-molecule drugs will bind covalently to the protein in the serum to form a complex recognised by certain molecules of human leukocyte antigen (HLA). Subsequently, these drugs are presented to the T cells to generate an immune response¹⁰
• Pharmacological interaction concept: This states that certain drugs that are unable to bind covalently to serum proteins, bind to HLA molecules and directly trigger the activation of T cells¹⁰
• Altered peptide concept: This hypothesises that drugs bind inside the binding pockets of HLA in such a way that alters the presentation of self-proteins to T cells. Consequently, these self-proteins are no longer recognised as self, leading to an immune response¹⁰

Symptoms of TEN and SJS

The initial symptoms (prodromal stage) of TEN and SJS can be nonspecific and usually occur within 4-28 days after continuous exposure to an implicated drug.¹⁰ These symptoms precede cutaneous and mucosal involvement. The symptoms include:

• Fever 
• Malaise 
• Sore throat and cough
• Rhinitis
• Anorexia
• Myalgia and arthralgia
• Erythematous macules
• Flaccid blisters with a positive Nikolsky sign 
• Acute conjunctivitis
• Eyelid oedema and crusts 
• Corneal ulceration

TEN and SJS also induce multisystem manifestations which include: pneumonia, acute respiratory distress syndrome, diarrhoea, melena, small bowel ulcerations, stenosis, stomatitis, vulvovaginitis, and urethritis.³

Why is it important to differentiate these conditions?

It is essential to differentiate between TEN and SJS because they are variants of the same condition but with different spectrums of severity. SJS represents the less severe end of the disease spectrum, and TEN signifies the more severe end.² Thus, the major distinguishing factor between these two conditions is the extent of skin infection. If the detachment from the epidermis is＜10% of the total body surface, it is classified as SJS. On the other hand, if the affected body surface area is >30%, it is considered TEN.²

Also, TEN is associated with ocular manifestations. These include: corneal ulcer, panophthalmitis, and even loss of vision, which requires ophthalmological intervention at an early stage.¹¹ Thus, differentiating TEN and SJS will assist with early medical consultation to prevent severe complications that can involve the respiratory system and gastrointestinal tract.  

Key differences between TEN and SJS

The following are the key differences between TEN and SJS according to the characteristic clinical features; 

Management and treatment of TEN and SJS

The management of TEN and SJS entails 3 measures: identification and removal of causative drugs (especially high-risk drugs), adoption of supportive care, and active intervention from healthcare professionals.¹² Early diagnosis and immediate cessation of the culprit drug is paramount because the course of these diseases, particularly TEN, is often rapid and fatal. 

The Algorithm for Drug Causality for Epidermal Necrolysis (ALDEN) has been proven to be an effective identifier of implicated drugs.⁶ Determining the prognosis of patients with TEN and SJS is also an essential step in the management of these conditions, as it can determine if the patients will be placed in intensive care or a burn unit.¹⁰ A prognostic score called SCORTEN (severity-of-illness score for toxic epidermal necrolysis) is the most effectively used tool for determining disease severity and prognosis of patients. People with a SCORTEN score of 3 and above should be managed in the intensive care unit. 

Supportive care is a crucial part of an effective treatment approach. This entails control of body temperature, proper hydration and replacement of electrolytes, pain control, preventing secondary infections or manifestations, etc.¹² The most efficacious treatment option is the use of cyclosporine and a combination of corticosteroids with human intravenous immunoglobulins (IVIg).¹⁰ Also, some of the ocular complications are triggered by inflammation. Thus, the use of ophthalmic steroids, extensive lubrication of the eyes, and daily erythromycin drops can be used to reduce inflammation.³

Summary 

• TEN and SJS are rare and severe dermatological conditions triggered by hypersensitivity reactions to specific implicated drugs
• Other causes of these conditions include infection with Mycoplasma pneumoniae, hepatitis A, and certain viral infections
• The initial symptoms of TEN and SJS commence at a prodromal phase and are characterised by fever, malaise, etc. This is followed by cutaneous manifestations and multisystem involvement
• TEN tends to be more severe and lethal than SJS. This is because TEN has  a wider surface body area involvement and spread of disease
• Mainstay management of TEN and SJS involves the identification of the culprit drug, if the cause, and aggressive supportive care depending on the severity of the disease
• There are no known ways to prevent these conditions. Therefore, prognostication and avoiding possible triggers are paramount in individuals with risk factors of TEN and SJS

FAQs

Can TEN and SJS be inherited?

SJS/TEN are not inherited conditions. However, genetic changes that increase the risk of developing SJS/TEN may be passed from generation to generation. This can also be influenced by exposure to the risk factors. 

How can TEN and SJS be diagnosed?

The diagnosis of TEN and SJS is mainly clinical. This involves the medical history, with emphasis on the use of drugs that elicit a skin reaction, and a thorough physical examination. A skin biopsy can also be done where a small piece of the skin affected by a rash is removed and examined. If positive, a skin biopsy reveals necrosis in all epidermal layers caused by apoptosis of keratinocytes with epidermal detachment. 

Do TEN and SJS occur in children?

Yes, children are predisposed to these conditions. However, infections like pneumonia, cold, or flu are the most likely cause of SJS in children, while drugs are the most common cause of TEN and SJS in adults.