Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous reactions that are best considered part of the same disease process. SJS and TEN are idiosyncratic reactions, typically to medications or infections, characterized by cutaneous epidermal skin necrosis along with involvement of at least two mucous membranes. In the past, erythema multiforme (EM, see Chapter 64) was classified into minor and major forms, the major form being synonymous with SJS. However, it is now recognized that despite histologic similarities, SJS and EM are best regarded as separate entities with distinct clinical presentations, outcomes, and causes.¹

SJS was first described by Stevens and Johnson in 1922 as a symptom complex in children involving “an eruptive fever associated with stomatitis and ophthalmia.”² In 1956, Lyell described a cutaneous process in adults as “an eruption resembling scalding of the skin” that he called toxic epidermal necrolysis (although this original report included at least one patient with what is now recognized as staphylococcal scalded skin syndrome [SSSS]).³ SJS and TEN are rare. The frequency (based on data from the FDA Adverse Event Reporting System [AERS] database) is approximately 1.9 cases of TEN per million inhabitants per year. Regional differences in drug prescription, genetic backgrounds, cancer/other comorbidities, and radiotherapy use may affect the incidence. The human immunodeficiency virus (HIV) population in particular has a 1000-fold increase in annual incidence compared to the general population.⁴ Although relatively rare, SJS and TEN often start in hospitalized patients, are managed within the inpatient setting, and are diagnostic considerations in many circumstances and therefore important entities to hospitalists and intensivists.

ETIOLOGY AND PATHOPHYSIOLOGY

SJS can be caused by medications or infectious agents, especially Mycoplasma pneumonia, but TEN is almost exclusively caused by medications. More than 100 drugs have been associated with SJS/TEN.¹ There is a smaller group of medications, that cause a disproportionate percentage of the cases. The most common categories of drugs that cause SJS and TEN include sulfonamides, other antibiotics, and antiepileptics. Allopurinol, particularly at a daily dose of >200 mg, is the most common individual inciting agent.⁴ Drugs causing SJS/TEN with shorter regimens include trimethoprim-sulfamethoxazole and other sulfonamides, aminopenicillins, cephalosporins, and quinolones. Drugs that are often given for longer duration that can cause SJS/TEN include lamotrigine, carbamazepine, phenytoin, phenobarbital, valproic acid, nonsteroidal anti-inflammatory drugs (particularly of the oxicam type) and allopurinol. With any of these medications, the highest risk is thought to occur in the first 2 months of treatment.⁴ It is also very important to recognize that carbamazepine, phenytoin, and phenobarbital have similar molecular structures and therefore a patient who reacts to one of these drugs may react to any of the others, and they should not be substituted for each other given the life-threatening nature of the reaction.

Other causes such as infections, certain triggering systemic diseases (such as inflammatory bowel disease), and immunizations are much less common and generally more difficult to prove with the exception of Mycoplasma pneumonia, which is now a well-established cause of SJS. In children, infections (particularly M. pneumonia) are a more commonly identified cause of SJS. Other potentially causal infections include herpes simplex virus (HSV), Mycoplasma tuberculosis, group A streptococci, hepatitis B, Epstein-Barr, and enteroviruses.^5,6 Of note, HSV is highly associated with EM, which in the past was thought to be on a spectrum with SJS but is now differentiated as a separate entity (see Differential diagnosis section below).

There is compelling evidence to suggest that a genetic susceptibility to SJS/TEN exists; those afflicted have an impaired capacity to detoxify reactive intermediate drug metabolites.⁷ HLA alleles have been associated with genetic susceptibility to SJS/TEN and may also play a role in pathogenesis. The HLA-B*1502 allele was first described in cases of carbamazepine-induced SJS/TEN in Han Chinese ancestral Asians. The risk is so high that the FDA recommends checking for HLA-B*1502 in at-risk Asian patients prior to starting carbamazepine.⁸ Interestingly, although HLA-B*1502 susceptibility has been determined to be population-dependent, other members of the larger HLA family (HLA-B75) have been associated to carbamazepine-induced SJS/TEN among other specific populations.⁹ Many other possible and/or confirmed HLA susceptibilities have been reported in various populations and with varying drug exposures as well as unique presentations. These include carbamazepine-induced reactions with HLA-B*1502, HLA-B*1511, and HLA-B*3101, abacavir-induced reactions with HLA-B*5701, allopurinol-induced reactions with HLA-B*5801, methazolamide-induced reactions with HLA-B*5901, nevirapine-induced reactions with DRB1*0101, oxicam-induced reactions with HLA-A2 and HLA-B12, and sulfonamide-induced reactions with HLA-A29, HLA-B12, and HLA-DR7.⁹

SJS/TEN presentations appear to be delayed-reaction hypersensitivity reactions. Hypotheses of immunopathogenesis center around T-cell–mediated massive apoptosis in keratinocytes, leading to epidermal necrolysis. Studies suggest possible roles of three pathways: the Fas-FasL interaction, perforin/granzyme B, and granulysin. The particular role of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells is an active area of research. Various cytokines and chemokines are also being identified that may participate in trafficking, proliferation, and regulation of activation.⁹ Of note, immunocompromised patients, especially those who are HIV positive, are known to be at particular risk for the development of SJS/TEN.

The histiologic features of SJS and TEN are full-thickness epidermal necrosis with sparse inflammatory cells. The severe epidermal necrosis is accompanied by incontinence of melanin pigment, colloid bodies, and subepidermal blister formation.¹⁰

SJS/TEN most commonly develops 2 to 8 weeks after drug exposure and is heralded by a prodrome of nonspecific constitutional symptoms that generally occur 1 to 14 days before the onset of necrotic mucosal or skin lesions. Children with SJS/TEN appear acutely ill. Fever and malaise are universal and are often accompanied by upper respiratory or gastrointestinal symptoms, or both.

Skin lesions, which may begin simultaneously or after the onset of mucosal lesions, consist of tender, red to dusky macules that are often targetoid. Lesions generally appear first on the presternal trunk and face, less commonly on the palms or soles. As they spread, the disease may ultimately affect the face, neck, trunk, proximal ends of the extremities, and palms and soles with rapid coalescence (see Figure 65-1). Blistering, often heralded by the development of central graying within the skin lesions, may develop within hours or after several days. Blistering may be limited or consist of widespread epidermal detachment. In the latter case, large areas of raw, bleeding dermis may be seen. Both SJS and TEN are characterized by epidermal detachment in addition to mucosal involvement, although the development of large sheets of epidermal detachment in the absence of mucosal involvement is more characteristic of TEN.¹¹ The frequent presence of overlapping clinical features in a given patient often makes definitive classification difficult. According to a consensus definition for the classification of SJS and TEN, epidermal detachment of 10% or less of total body surface area is classified as SJS, greater than 30% as TEN, and between 10% and 30% as SJS-TEN overlap.¹⁰ Other potential systemic complications of SJS/TEN include generalized lymphadenopathy, hepatosplenomegaly, hepatitis, arthritis, and arthralgias. Less common findings are myocarditis, pancreatitis, pulmonary complications (especially pneumonia and pneumothorax), and nephritis.¹²

At least two mucosa are involved and most commonly include the intraoral and ocular mucosa but may also include the urethra, anus, vaginal vault, and upper aerodigestive tract. M. pneumonia can lead to typical SJS or more rarely cause an atypical form of SJS that still involves at least two mucous membranes but lacks the classic cutaneous lesions.^5,6 Therefore isolated and severe mucositis should always prompt serologic or polymerase chain reaction testing for M. pneumonia, particularly if there is ocular involvement. Classically, hemorrhagic crusts develop on the lips (Figure 65-1), and painful stomatitis leads to decreased oral intake. The skin of the conjunctivae also sloughs, leading to a purulent conjunctivitis. As the denuded mucosa of the eye attempts to heal, it can form synechea and either cause the lids to adhere to each other or the palpebral conjunctivae to adhere to the bulbar conjunctiva, which can lead to blindness. Genital mucosal involvement is complicated by pain, bleeding, and possible scarring. Respiratory or gastrointestinal involvement may also occur in more severe cases.^10,11