Andrea Y. Ang, Florentino E. Palmon and Edward J. Holland

Introduction

Erythema multiforme (EM), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are considered as a spectrum of epidermal bullous diseases involving the skin and mucous membranes, usually triggered by drugs or infection. Although rare diseases, they are important since they cause high mortality and morbidity, with ocular involvement often being the most serious long-term sequela. Initial management involves early recognition, prompt hospitalization, and immediate cessation of the offending agent. During the acute self-limited course of the illness, management is primarily supportive in providing fluid management and prevention of sepsis. During the acute stage, it is important to manage the ocular surface inflammation aggressively with supportive treatment, so as to minimize the development of cicatricial changes that lead to chronic ocular surface disease.

History

In 1866, the Austrian dermatologist Ferdinand von Hebra first described erythema multiforme as a self-limited cutaneous disease characterized by multiform skin lesions.¹ In association with the erythematous skin lesions, his findings included a severe stomatitis and purulent conjunctivitis. In 1922, two American pediatricians, Stevens and Johnson, described two boys with a more severe mucocutaneous disease with ophthalmologic manifestations, naming the disease eruptive fever with stomatitis and ophthalmia.² This nomenclature was not adopted. However, since that time, erythema multiforme major has been most commonly referred to as Stevens–Johnson syndrome. In 1950, Thomas suggested the division of erythema multiforme into two forms: minor (von Hebra) and major (SJS).³ In 1956, Lyell introduced the term toxic epidermal necrolysis, a condition characterized by more extensive skin loss in conjunction with mucous membrane involvement.⁴

Classification

There was confusion in the nomenclature and diagnostic criteria for the erythema multiforme spectrum of diseases until an international classification was adopted in 1993.⁵ Traditionally, erythema multiforme was divided into minor and major forms, with the minor form only involving skin, with no or minimal mucous membrane involvement and not involving the eye. Table 30.1 outlines the diagnostic criteria for bullous skin diseases.⁶ Although the terms EM major and SJS are often used interchangeably, international collaborators have now differentiated them by their etiology and pattern of cutaneous lesions.⁷ The major etiologic factor for EM major (or bullous EM) is herpes simplex virus (HSV), compared to drug-induced SJS. An international consensus collaboration further classified the overlap between SJS and TEN. They defined five categories based on the pattern of skin lesions and extent of epidermal detachment as shown in Table 30.2.⁵

Incidence

Although EM/SJS/TEN are rare conditions, they are important because they cause high mortality and morbidity. Chan (USA) reported an overall incidence of these diseases at 4.2 per million person-years (TEN 0.5 per million person-years),⁶ and Rzany (Germany) reported an overall incidence of 1.89 per million person-years.⁸ Schöpf (Germany) reported an incidence of SJS at 1.1 per million person-years and incidence of TEN at 0.93 per million person-years.⁹ Roujeau (France) reported an incidence of TEN at 1.2 to 1.3 per million person-years.¹⁰ The reported mortality rate is 1% for EM, 1% to 7% for SJS, and 30% to 45% for TEN.^9–11 Both the incidence and the mortality appear to be higher in immunocompromised patients with these risks correlated with weaker immune function.¹² EM is more common in males, whereas TEN is more common in women, with a ratio ranging from 1.5 : 1 to 2.0 : 1.^9–11 Although these conditions can occur at any age, EM and SJS tends to occur in younger patients in their second to third decades, whereas TEN occurs in older patients in their fifth to seventh decades.^9–11

Etiology

Drugs and infections are the most common inciting causes of disease, as shown in Table 30.3. Drug-related reactions typically begin within 3 weeks of initiation of therapy. In cases of re-exposure to the drug, the reaction may begin within hours of restarting the therapy.⁶ TEN is usually drug-related. Drugs are an important cause of SJS, but infections, or a combination of infections and drugs has also been implicated. Infections, especially viral, are the most common cause of EM. In large epidemiology studies, drugs accounted for 89% to 95.5% of cases of TEN,^9,10 54% to 64% of cases of SJS,^9,11 and 18% for EM major.¹¹ In the international prospective SCAR (severe cutaneous adverse reactions) study, recent or recurrent herpes was the principal risk factor for EM major (etiologic fractions of 29% and 17%, respectively) and had a role in SJS (etiologic fractions of 6% and 10%) but not in overlap cases or TEN.¹¹ Mycoplasma pneumoniae has also been associated with EM Major in several studies.^11,13

In the SCAR study, the use of antibacterial sulfonamides, anticonvulsants, oxicam nonsteroidal anti-inflammatory drugs (NSAIDs), allopurinol, chlormezanone, and corticosteroids were associated with large increases in the risk of SJS or TEN.¹⁴ However, it is important to note that these reactions are rare, since for each of these drugs the excess risk did not exceed five cases per million users per week. Among drugs usually used for months or years, the increased risk was confined largely to the first 2 months of treatment. Table 30.4 lists drugs that have been associated with these diseases.

Pathogenesis

The exact pathophysiologic mechanism of EM/SJS/TEN remains unknown. Prevailing evidence indicates an immune-mediated response, in particular those mediated by memory cytotoxic T cells, to drugs and infections. Histologically, keratinocyte death occurs from extensive apoptosis.¹⁵ The proposed initiating mechanism involves the interaction between Fas and Fas ligand (FasL), which is either membrane bound on keratinocytes or soluble.¹⁶ Activation of the Fas signaling cascade leads to widespread keratinocyte apoptosis and subsequent epithelial necrosis. It has been suggested that soluble FasL is secreted by peripheral blood mononuclear cells and is elevated in EM and TEN patients.¹⁷ Other studies have also linked perforin, a pore-making monomeric granule released from natural killer T lymphocytes, which is thought to initiate the keratinolysis seen early in the development of SJS.¹⁸ Granulysin has also been implicated as a key mediator for disseminated keratinocyte death in SJS/TEN. Granulysin levels are much higher in patients with SJS/TEN, compared to healthy controls, and also correlate with clinical severity.¹⁹

Genetic factors may also play a role in the development of erythema multiforme disorders. Slow acetylators and those taking medications, such as azoles, protease inhibitors, serotonin-specific reuptake inhibitors, and quinolones are at increased risk of developing SJS. The reduced rate of acetylation causes the accumulation of reactive metabolites that induce cell-mediated cytotoxic reactions against the epidermis, resulting in keratinocyte apoptosis.¹²

In studies in Western populations,14,20 antibiotics, particularly sulfonamides, are the most common drug trigger. In the largest Asian study by Chang et al.,¹³ anticonvulsants, particularly carbamazepine, and allopurinol were the most common drug triggers. A study by Chung et al.²¹ found a strong association in Han Chinese between the human leukocyte antigen (HLA) B*1502 and SJS induced by carbamazepine. Another study showed that HLA-B*5801 is highly associated with allopurinol-induced SJS/TEN.²² These associations suggest the importance of pharmacogenetic mechanisms on the risk of developing SJS/TEN.

Histopathology

The initial diagnosis of EM/SJS/TEN is based on clinical presentation; however, skin biopsies should be taken for both routine histopathology and direct immunofluorescence in order to distinguish these conditions from autoimmune blistering disorders. The typical histopathology of EM/SJS/TEN is characterized by vacuolization of epidermal cells and necrosis of keratinocytes within the epidermis, along with dermoepidermal detachment and perivascular lymphocytic infiltration.²³ The dermal infiltrate is more pronounced in EM major, compared to SJS or TEN.²⁴ In TEN, subepidermal blistering associated with full-thickness epidermal necrosis occurs.

Clinical Findings