Widespread Peeling Rash

In the early 20th century, the American pediatricians Mason Stevens and Chambliss Johnson published 2 case studies of skin detachment with mucosal involvement, later dubbed Stevens-Johnson syndrome (SJS).1-3 Several decades later, Alan Lyell first coined the term toxic epidermal necrolysis...

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In the early 20th century, the American pediatricians Mason Stevens and Chambliss Johnson published 2 case studies of skin detachment with mucosal involvement, later dubbed Stevens-Johnson syndrome (SJS).^1-3 Several decades later, Alan Lyell first coined the term toxic epidermal necrolysis (TEN).^2,4 In 1993, consensus-based definitions of severe cutaneous adverse reactions (SCAR) were introduced, noting subgroups of severe bullous skin reactions including SJS, TEN, and SJS/TEN overlap.² The distinction between the 3 categories is defined by the area of skin involvement (Table). The term SJS/TEN is often used to describe the entire disease spectrum.^2,3

Table. Definition of SCAR Based on Area of Skin Involvement^2,3

Condition	Percent (%) Skin Involvement
Stevens-Johnson syndrome	<10
Toxic epidermal necrolysis	>30
SJS/TEN overlap	10-30

Stevens-Johnson syndrome/TEN is a rare disease typically associated with a drug reaction. In the United States, estimates of incidence per million persons include 8.61 to 9.69 for SJS, 1.46 to 1.84 for SJS/TEN overlap, and 1.58 to 2.26 for TEN.^2,5 Stevens-Johnson syndrome/TEN is associated with hematologic malignancies, liver and kidney disease, and certain infections including HIV.² In the adult population, mortality rates for SJS, SJS/TEN overlap, and TEN are approximately 4.8%, 19.4%, and 14.8%, respectively, although some estimates note that the mortality rate for TEN may be as high as 30%.² Mortality rates in children with TEN are lower with a range of 0% to 7.5%.^2,6 While HIV is an independent risk factor for SJS/TEN, several drugs frequently prescribed to this population — including sulfonamides and nevirapine — exacerbate the risk.²

Known drugs associated with an SJS/TEN reaction include antibacterial sulfonamides, antiepileptic drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) of the oxicam type, allopurinol, chlormezanone, and corticosteroids.² The risk of SJS/TEN is compounded by an individual’s genetic predisposition, including specific human leukocyte antigen (HLA) alleles, drug metabolism characteristics, and T cell clonotypes.³ Stevens-Johnson syndrome/TEN is a delayed-type drug hypersensitivity reaction with a typical latency time of 4 weeks, although symptoms may be seen after 8 weeks in vulnerable individuals and even 30 weeks in some cases.^2,3 Symptoms may also occur a few days after drug withdrawal for long-half-life drugs or, rarely, within hours of rechallenge with the same drug.³

Initial symptoms are nonspecific, flu-like, and may precede cutaneous manifestations by a few days. Early cutaneous involvement typically includes the presternal region of the trunk, face, and proximal parts of the limbs. Individual lesions are irregularly shaped, erythematous, dusky dark purpuric macules. These atypical targetoid lesions have a necrotic center and commonly coalesce. Typically, at least 2 mucous membrane sites are involved.³ Patients are classified along the spectrum of SJS/TEN based on the visibly blistering areas of the skin as well as those with a positive Nikolsky sign. Histologically, the lesions show massive epidermal necrosis and sparse dermal inflammatory infiltrate.² Systemic manifestations of this acute skin failure may include pulmonary, renal, and gastrointestinal involvement. ³ The severity of the condition and its associated mortality can be approximated with the SJS/TEN-specific severity-of-illness score (SCORTEN). ⁷

The differential diagnosis for SJS/TEN includes erythema multiforme (EM), autoimmune bullous diseases (including linear IgA dermatosis), autoimmune disease (including bullous lupus erythematosus), staphylococcal scalded skin syndrome (SSSS), graft-vs-host disease (GVHD), generalized fixed bullous drug eruption, and acute generalized exanthematous pustulosis (AGEP). Clinically distinct from SJS/TEN, EM is typically noted in an acral distribution with typical and/or raised atypical lesions and is frequently associated with herpes simplex virus (HSV).² When clinical presentation is nonspecific, histopathology is often necessary to distinguish SJS/TEN from other bullous disorders. For example, SSSS shows intraepidermal cleavage compared with the subepidermal cleavage noted in TEN.³ Clinical history and direct- and indirect- immunofluorescence and serology can also delineate the disorder from similar presentations like bullous systemic lupus erythematosus.²

Acute management of suspected SJS/TEN includes immediate cessation of any potentially causative drugs followed by referral to specialized units such as burn centers. Supportive care measures include airway protection, fluid replacement, nutritional support, pain management, coagulation prophylaxis, infection monitoring, and psychological support.³ While no established treatment protocol for SJS/TEN exists, medical treatment options include the use of intravenous immunoglobulin, cyclosporine, systemic corticosteroids, and tumor necrosis factor (TNF) inhibitors.³ Debridement is no longer recommended because of concern for hypertrophic scarring, and the detached epidermis is instead utilized as a natural barrier supporting re-epithelialization.

 Specialized care is often required for mucous membrane involvement, including considerations for ocular, oropharyngeal, and genital management.³ Long-term sequelae include cutaneous concerns such as postinflammatory dyspigmentation and abnormal scarring, ocular sequelae (affecting 20%-75% of survivors), and oral and dental sequelae (including a Sjögren-like sicca syndrome in 40% of survivors). Chronic pulmonary, renal, gastrointestinal, hepatic, and psychological sequelae are also cause for concern. Survivors should permanently refrain from the use of any suspected drug and regularly receive multidisciplinary follow-up guided by a coordinating physician, typically a dermatologist.⁸

All suspicious medications were discontinued in the patient in this case. The patient was admitted to the hospital and provided specialized care.

Rosemary Demet, is a medical student at Baylor College of Medicine in Houston, Texas; Tara Braun, MD, is a dermatologist at Elite Dermatology in Houston, Texas.

References

1. Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia: report of two cases in children. Am J Dis Child. 1922;24(6):526-533. doi:10.1001/archpedi.1922.04120120077005

2. Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Current perspectives on Stevens-Johnson syndrome and toxic epidermal necrolysis. Clin Rev Allergy Immunol. 2018;54(1):147-176. doi:10.1007/s12016-017-8654-z

3. Dodiuk-Gad RP, Chung W, Valeyrie-Allanore L, Shear NH. Stevens-johnson syndrome and toxic epidermal necrolysis: an update. Am J Clin Dermatol. 2015;16(6):475-493. doi:10.1007/s40257-015-0158-0

4. Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol. 1956;68(11):355-361. doi:10.1111/j.1365-2133.1956.tb12766.x.

5. Hsu DY, Brieva J, Silverberg NB, Silverberg JI. Morbidity and mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis in United States adults.  J Invest Dermatol. 2016;136(7):1387-1397. doi:10.1016/j.jid.2016.03.023

6. Hsu DY, Brieva J, Silverberg NB, Paller AS, Silverberg JI. Pediatric Stevens-Johnson syndrome and toxic epidermal necrolysis in the United States. J Am Acad Dermatol. 2017;76(5):811-817.e4. doi:10.1016/j.jaad.2016.12.024.

7. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: A severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;115(2):149-153. doi:10.1046/j.1523-1747.2000.00061.x

8. Lee HY, Walsh SA, Creamer D. Long-term complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN): the spectrum of chronic problems in patients who survive an episode of SJS/TEN necessitates multidisciplinary follow-up. Br J Dermatol. 2017;177(4):924-935. doi:10.1111/bjd.15360.