Stevens-Johnson syndrome and toxic epidermal necrolysis are acute, rare, and potentially fatal skin reactions involving loss of skin and, in some cases, mucosal membranes accompanied by systemic symptoms. Medications are causative in over 80 percent of cases. Stevens-Johnson syndrome and toxic epidermal necrolysis are distinguished based on the extent of the detached skin surface area. This activity illustrates the evaluation and treatment of Stevens-Johnson syndrome and of toxic epidermal necrolysis and reviews the role of the interprofessional team in managing those with these conditions.
Describe the difference between Stevens-Johnson syndrome and toxic epidermal necrolysis.
Summarize differential diagnoses of Stevens-Johnson syndrome and of toxic epidermal necrolysis.
Review the treatment options for Stevens-Johnson syndrome and toxic epidermal necrolysis.
Explain the role of interprofessional team members in optimizing collaboration and communication to ensure patients with Stevens-Johnson syndrome or toxic epidermal necrolysis receive high-quality care, which will lead to enhanced outcomes.
Previously known as Lyell syndrome, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are variants of the same condition and are distinct from erythema multiforme major staphylococcal scalded skin syndrome, and other drug eruptions.
Stevens-Johnson syndrome/toxic epidermal necrolysis is a rare, acute, serious, and potentially fatal skin reaction in which there are sheet-like skin and mucosal loss accompanied by systemic symptoms. Medications are causative in over 80% of cases.
Stevens-Johnson syndrome/toxic epidermal necrolysis is classified by the extent of the detached skin surface area.
Stevens-Johnson syndrome: less than 10% body surface area
Overlap Stevens-Johnson syndrome/toxic epidermal necrolysis: 10% to 30% body surface area
Toxic epidermal necrolysis more than 30% body surface area
Stevens-Johnson syndrome/toxic epidermal necrolysis is a rare and unpredictable reaction to medication that involves drug-specific CD8+ cytotoxic lymphocytes, the Fas-Fas ligand (FasL) pathway of apoptosis, and granule-mediated exocytosis and tumor necrosis factor-alfa (TNF–alpha)/death receptor pathway. 
Current theories address the following mechanisms, among others.
Granulysin, found in the cytotoxic granules, is the main cause of keratinocyte apoptosis.
Fas–FasL, expressed on the activated cytotoxic T cells, can also destroy keratinocytes via the production of intracellular caspases.
Cytotoxic T cells exocytose perforin and granzyme B, which create channels in the target cell membrane activating the caspases.
TNF–alpha may cause apoptosis or protect from it.
Nitrous oxide (NO) induced by TNF–alpha and interferon (IFN)–alpha may stimulate caspases.
Stevens-Johnson syndrome/toxic epidermal necrolysis is estimated to affect two to seven per million people each year. Stevens-Johnson syndrome is three times more common than toxic epidermal necrolysis. Stevens-Johnson syndrome/toxic epidermal necrolysis can affect anyone with a genetic predisposition: any age, either sex, and all races, although it is more common in older people and women. It is much more likely to occur in people infected with the human immunodeficiency virus (HIV), with an estimated incidence of 1/1000.
Numerous medications have been reported to trigger Stevens-Johnson syndrome/toxic epidermal necrolysis.
Stevens-Johnson syndrome/toxic epidermal necrolysis are rarely associated with vaccination and infections such as mycoplasma, cytomegalovirus, and dengue.
The drugs that most commonly cause Stevens-Johnson syndrome/toxic epidermal necrolysis are:
Nonsteroidal anti-inflammatory drugs (NSAIDs) (oxicam type mainly)
Genetic factors include human leukocyte antigen (HLA) allotypes that lead to an increased risk of Stevens-Johnson syndrome/toxic epidermal necrolysis when exposed to aromatic anticonvulsants and allopurinol. Family members of a patient with Stevens-Johnson syndrome/toxic epidermal necrolysis should be advised that they are at risk of developing the disease and should be cautious about taking any medications associated with the disease.
To date, findings have included the risk of Stevens-Johnson syndrome/toxic epidermal necrolysis in:
Han Chinese, Thai, Malaysian, and South Indian people if they carry HLA-B*1502 and take aromatic anticonvulsants.
Han Chinese if they carry HLA-B*5801 and take allopurinol
Europeans if they carry HLA-B*5701 and take abacavir, or if they carry HLA-A*3101 and take carbamazepine.
The initial step for Stevens-Johnson syndrome/toxic epidermal necrolysis may be interaction/binding of a drug-associated antigen or metabolite with the major histocompatibility complex (MHC) type 1 or cellular peptide to form an immunogenic compound. The exact mechanism is speculative.
Stevens-Johnson syndrome/toxic epidermal necrolysis is T–cell-mediated.
CD8+ cells are present in blister fluid and may induce keratinocyte apoptosis.
Other cells of the innate immune system play a role.
CD40 ligand cells are also present and may induce the release of TNF–alpha, nitrous oxide, interleukin 8 (IL-8), and cell adhesion antibodies. TNF–alpha also induces apoptosis.
Both Th1 and Th2 cytokines are present.
Other cells implicated in Stevens-Johnson syndrome/toxic epidermal necrolysis include macrophages, neutrophils, and natural killer (NK) cells.
The pharmacologic interaction of drugs with the immune system could result in binding of the responsible drug to MHC-1 and the T cell receptor. An alternative theory is a pro-hapten concept, in which drug metabolites become immunogenic and stimulate the immune system.
Histology of the skin reveals necrosis of keratinocytes, epidermal (or epithelial) necrosis, and mild lymphocytic dermal infiltration. Direct immune fluorescence is negative.
The drugs that precipitate Stevens-Johnson syndrome/toxic epidermal necrolysis tend to have long half-lives and are nearly always taken systemically. Stevens-Johnson syndrome/toxic epidermal necrolysis can develop within a few days to eight weeks after starting a new drug. A subsequent exposure can result in symptoms within a few hours.
History and Physical
The illness begins with nonspecific symptoms such as fever and malaise, upper respiratory tract symptoms such as a cough, rhinitis, sore eyes, and myalgia. Over the next three to four days, a blistering rash and erosions appear on the face, trunk, limbs, and mucosal surfaces.
Erythematous, targetoid, annular, or purpuric macules
Large painful erosions
Nikolsky-positive (lateral pressure on the skin results in shedding of the epidermis)
Early on, toxic epidermal necrolysis displays widespread tender erythroderma and erosions (with or without targetoid rash), whereas Stevens-Johnson syndrome is characterized more by targetoid rash, with fewer areas of denudation.
Mucosal ulceration and erosions can involve lips, mouth, pharynx, esophagus and gastrointestinal tract, eyes, genitals, upper respiratory tract. About half of patients have involvement of three mucosal sites.
The patient is very ill, anxious, and in pain. Liver, kidneys, lungs, bone marrow, and joints may be affected by Stevens-Johnson syndrome/toxic epidermal necrolysis. Typical symptoms include:
Fever, malaise, headache, anorexia, pharyngitis
Symptoms due to acute dysfunction of ocular, pulmonary, cardiovascular, gastrointestinal, renal, and hematological systems.
Features may overlap with other severe cutaneous adverse reactions (SCAR), such as acute generalized exanthematous pustulosis (causing subcorneal pustules) and drug hypersensitivity syndrome (causing a morbilliform eruption and involving other organs).
Investigations may include:
Urgent frozen sections of skin biopsy: full-thickness skin necrosis
Liver function tests (LFT): elevated transaminases, hypoalbuminemia
Renal function: microalbuminuria, renal tubular enzymes in urine, reduced glomerular filtration, rising creatinine and urea, hyponatremia
Pulmonary function: bronchial mucosal sloughing on bronchoscopy, interstitial infiltrates on chest x-ray
Cardiac function: abnormal ECG and imaging.
The severity of Stevens-Johnson syndrome/toxic epidermal necrolysis is assessed using SCORTEN. One point is scored for each of the following seven criteria at admission.
Age older than 40 years
Presence of a malignancy
Heart rate of more than 120 bpm
Initial percentage of epidermal detachment greater than 10%
Serum urea level greater than 10 mmol/L
Serum glucose level greater than 14 mmol/L
Serum bicarbonate level less than 20 mmol/L
The risk of dying from Stevens-Johnson syndrome/toxic epidermal necrolysis depends on the score. The mortality rate is more than 40 times higher in those with bicarbonate levels less than 20 mmol/L compared with those with higher levels. A SCORTEN ranges with their associated mortality (in %) are as follows: score 0-1 (3.2%), score 2 (12.1%), score 3 (35.3%), score 4 (58.3%), and score 5 (>90%).
In patients on multiple drugs known to cause Stevens-Johnson syndrome/toxic epidermal necrolysis, the algorithm ALDEN has been developed to determine the likely cause.
The period between drug intake and the onset of reaction (index day): 5 to 28 days (score of 3), 29 to 56 days (2), 1 to 4 days (1), more than 56 days (–1), index day (–3) for the first episode; 1 to 4 days (score of 3), 5 to 56 days (1) for a subsequent episode
Presence of drug on index day or within five times elimination half-life: stopped (1), unknown (0), stopped earlier (–1), continued beyond index day (–2)
Previous history of adverse reaction to the same drug: Stevens-Johnson syndrome/toxic epidermal necrolysis (4), Stevens-Johnson syndrome/toxic epidermal necrolysis to a similar drug (2), other reaction to same or similar drug (1), none (0), previous use without reaction (–2)
The notoriety of the drug, according to SCAR study: high risk (3), lower risk (2), possible risk (1), under surveillance or new drug (0), no evidence of association (–1)
Other possible cause: infection (–1), another drug that high risk (–1 for each other drug)
Treatment / Management
Patients should undergo interprofessional assessment in a specialized hospital environment. 
Plastic surgery or burns specialist
Care of a patient with Stevens-Johnson syndrome/toxic epidermal necrolysis requires supportive care , including:
Cessation of the suspected causative drug(s)
Hospital admission: preferably to an intensive care and/or burn unit
Fluid replacement (crystalloid)
Nutritional assessment: may require nasogastric tube feeding
Temperature control: warm environment, emergency blanket
Supplemental oxygen and, in some cases, intubation with mechanical ventilation
Skincare requires daily examination of skin and mucosal surfaces for infection, non-adherent dressings, and avoidance of trauma to the skin. Mucosal surfaces require careful cleansing and topical anesthetics.
Gentle removal of necrotic skin/mucosal tissue
Culture of skin lesions, axillae, and groins every two days
Antibiotics may be required for secondary infection but are best avoided prophylactically.
It is unknown whether systemic corticosteroids are beneficial, but they are often prescribed in high doses for the first three to five days of admission. Granulocyte colony-stimulating factor (G-CSF) may be of benefit in patients with severe neutropenia.
Other drugs reported effective include systemic corticosteroids, ciclosporin, TNF-alpha inhibitors , N-acetylcysteine, and intravenous immunoglobulins. Their role remains controversial.
Other acute exfoliative conditions that may need consideration include:
Other severe cutaneous adverse reactions (SCAR) to drugs, such as drug hypersensitivity syndrome (DHS), acute generalized exanthematous pustulosis (AGEP)
Stevens-Johnson syndrome/toxic epidermal necrolysis is potentially very serious with high mortality, predicted by the extent and severity at presentation (see SCORTEN and ALDEN above).
Mean adjusted mortality reported for the Nationwide Inpatient Sample 2009-2012 (US) was 4.8% for SJS, 19.4% for SJS/TEN overlap, and 14.8% for TEN.
In Créteil, France, 66 of 361 patients diagnosed with Stevens-Johnson syndrome/toxic epidermal necrolysis died (18%): 2% with SJS, 12% with SJS/TEN overlap, and 26% with TEN. There has been a trend towards improved mortality in recent years, attributed mainly to better supportive care than in earlier decades.
In the acute phase, sepsis is the most common serious risk of Stevens-Johnson syndrome/toxic epidermal necrolysis. Organ failure may occur, including pulmonary, hepatic, and renal systems.
The most common long-term complications of Stevens-Johnson syndrome/toxic epidermal necrolysis are ocular (including blindness), cutaneous (pigmentary changes and scarring), and renal. Mucosal involvement with blisters and erosions can lead to strictures and scarring.
The care of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis is multidisciplinary. Patients with blistering involving greater than 10% of the skin surface are usually admitted to intensive care units or burns units for supportive care.
Pearls and Other Issues
Death is mainly due to sepsis and multiorgan failure. Contributing causes are:
Myocardial infarction and pulmonary edema
People who have survived Stevens-Johnson syndrome/toxic epidermal necrolysis must avoid the causative drug or structurally related medicines as Stevens-Johnson syndrome/toxic epidermal necrolysis may recur. Cross-reactions can occur between:
Anticonvulsants carbamazepine, phenytoin, lamotrigine and phenobarbital
Beta-lactam antibiotics penicillin, cephalosporin, and carbapenem
The management of SJS is interprofessional. A number of specialists are usually involved in the care of these patients, including a dermatologist, intensivist, ophthalmologist, pulmonologist, nephrologist, plastic surgeon, and gastroenterologist, functioning as an interprofessional team. The acute care of these patients is provided by wound care. The pharmacist must also closely assess the medications that the patient is receiving to prevent exacerbation of the disorder or determine if any of the patient's medications could be the trigger for the condition. Even after treatment, these patients may have severe cosmetic deficits and may require mental health counseling. If the lesions occur across joints, the patient may benefit from physical therapy to restore function and muscle strength. The patient has to be educated on the use of ocular lubricants because of the sicca-like syndrome. Many patients do lose weight after suffering a severe reaction and should be referred to a dietitian. Following discharge, the patients need long-term follow-up to ensure that there are no functional deficits, including vision loss. Once a patient has suffered an SJS, it is highly recommended that the patient wear a warning bracelet indicating the toxic agent or allergen. [Level 5]
The outcomes of patients with SJS depend on the extent and severity of skin involvement. For those with a mild eruption, the lesions usually heal in 12 to 16 weeks. Mild scarring may occur, but there is usually no functional loss unless the eyes and other mucous membranes are involved. When the involved skin area is more than 20%, mortality rates of 1 to 27% have been reported. The presence of concomitant bacterial infection can increase mortality rates. Factors that adversely affect the outcome include advanced age, leucopenia, presence of a malignancy, renal dysfunction, hyperglycemia, and more than 10% BSA involvement. Survivors of SJS may develop inverted eyelids, sicca-like syndrome, visual loss, and corneal neovascularization, but n interprofessional approach will lead to better outcomes. [Level 5]
(Click Image to Enlarge)
Erythematous, Purpuric, Macules, targetoid lesions, Stevens Johnson Syndrome
Contributed by DermNetNZ
(Click Image to Enlarge)
Widespread early morbilliform eruption with flaccid bullae in patient with toxic epidermal necrolysis
Contributed by DermNetNZ
(Click Image to Enlarge)
Healing Toxic epidermal necrolysis
Contributed by Dr. Shyam Verma, MBBS, DVD, FRCP, FAAD, Vadodara, India
Iyer G,Srinivasan B,Agarwal S,Ravindran R,Rishi E,Rishi P,Krishnamoorthy S, Boston Type 2 keratoprosthesis- mid term outcomes from a tertiary eye care centre in India. The ocular surface. 2018 Aug 26 [PubMed PMID: 30157458]
Frey N,Bodmer M,Bircher A,Jick SS,Meier CR,Spoendlin J, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Association with Commonly Prescribed Drugs in Outpatient Care Other than Anti-Epileptic Drugs and Antibiotics: A Population-Based Case-Control Study. Drug safety. 2018 Aug 16 [PubMed PMID: 30112729]
Sato S,Kanbe T,Tamaki Z,Furuichi M,Uejima Y,Suganuma E,Takano T,Kawano Y, Clinical features of Stevens-Johnson syndrome and toxic epidermal necrolysis. Pediatrics international : official journal of the Japan Pediatric Society. 2018 Aug [PubMed PMID: 29888432]
Velasco-Tirado V,Alonso-Sardón M,Cosano-Quero A,Romero-Alegría Á,Sánchez-Los Arcos L,López-Bernus A,Pardo-Lledías J,Belhassen-García M, Life-threatening dermatoses: Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Impact on the Spanish public health system (2010-2015). PloS one. 2018 [PubMed PMID: 29912947]
Safiri S,Ashrafi-Asgarabad A, The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptic drugs: Comment on data sparsity. Epilepsia. 2018 May [PubMed PMID: 29723404]
Tangamornsuksan W,Lohitnavy M, Association Between HLA-B*1301 and Dapsone-Induced Cutaneous Adverse Drug Reactions: A Systematic Review and Meta-analysis. JAMA dermatology. 2018 Apr 1 [PubMed PMID: 29541744]
Lerma V,Macías M,Toro R,Moscoso A,Alonso Y,Hernández O,de Abajo FJ, Care in patients with epidermal necrolysis in burn units. A nursing perspective. Burns : journal of the International Society for Burn Injuries. 2018 Jul 10 [PubMed PMID: 30005991]
Schneider JA,Cohen PR, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures. Advances in therapy. 2017 Jun [PubMed PMID: 28439852]
Zhang S,Tang S,Li S,Pan Y,Ding Y, Biologic TNF-alpha inhibitors in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis: a systemic review. The Journal of dermatological treatment. 2020 Feb; [PubMed PMID: 30702955]
Schwartz RA,McDonough PH,Lee BW, Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment. Journal of the American Academy of Dermatology. 2013 Aug; [PubMed PMID: 23866879]
Hsu DY,Brieva J,Silverberg NB,Silverberg JI, Morbidity and Mortality of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in United States Adults. The Journal of investigative dermatology. 2016 Jul; [PubMed PMID: 27039263]
Bettuzzi T,Penso L,de Prost N,Hemery F,Hua C,Colin A,Mekontso-Dessap A,Fardet L,Chosidow O,Wolkenstein P,Sbidian E,Ingen-Housz-Oro S, Trends in mortality rates for Stevens-Johnson syndrome and toxic epidermal necrolysis: experience of a single centre in France between 1997 and 2017. The British journal of dermatology. 2020 Jan; [PubMed PMID: 31323695]
Papp A,Sikora S,Evans M,Song D,Kirchhof M,Miliszewski M,Dutz J, Treatment of toxic epidermal necrolysis by a multidisciplinary team. A review of literature and treatment results. Burns : journal of the International Society for Burn Injuries. 2018 Jun [PubMed PMID: 29627131]
Antoon JW,Goldman JL,Shah SS,Lee B, A Retrospective Cohort Study of the Management and Outcomes of Children Hospitalized with Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. The journal of allergy and clinical immunology. In practice. 2018 May 30 [PubMed PMID: 29859332]
Antoon JW,Goldman JL,Lee B,Schwartz A, Incidence, outcomes, and resource use in children with Stevens-Johnson syndrome and toxic epidermal necrolysis. Pediatric dermatology. 2018 Mar [PubMed PMID: 29315761]