Stevens-Johnson syndrome: Pathogenesis, diagnosis

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SJS, also known as erythema multiforme major, lies on a continuum between erythema multiforme minor ... respiratory tract symptoms lasting up to 2 weeks.
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Annals of Medicine. 2008; 40: 129–138

REVIEW ARTICLE

Stevens-Johnson syndrome: Pathogenesis, diagnosis, and management

RIBHI HAZIN1, OMAR A. IBRAHIMI2, MOUSTAFA I. HAZIN3 & ARASH KIMYAI-ASADI4 1

Harvard University, Faculty of Arts and Sciences, Cambridge, MA, USA, 2Harvard Medical School, Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA, 3Department of Internal Medicine, St. Joseph’s Hospital & Medical Center, Phoenix, AZ, USA, and 4DermSurgery Associates, Houston, Texas, USA

Abstract Cutaneous drug reactions are the most common type of adverse drug reaction. These reactions, ranging from simple pruritic eruptions to potentially life-threatening events, are a significant cause of iatrogenic morbidity and mortality. StevensJohnson syndrome (SJS) is a serious and potentially life-threatening cutaneous drug reaction. Although progress has been made in the management of SJS through early detection, prompt hospitalization, and immediate cessation of offending agents, the prevalence of permanent disabilities associated with SJS remains unchanged. Nevertheless, despite being a problem that is global in scope, government and health care agencies worldwide have yet to find a consensus on either diagnostic criteria or therapy for this disorder. Here, we provide the internist and emergency room physician with a brief review the SJS literature and summarize the latest recommended interventions with the hope of improving early recognition of this disease and prevention of permanent sequelae and mortality that frequently complicate SJS.

Key words: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, intravenous immunoglobulins, adverse drug reaction, drug hypersensitivity, dermatological emergencies, mucocutaneous lesions, HLA B1501/HLA B1502, keratinocyte apoptosis

Introduction Stevens-Johnson Syndrome (SJS) is a life-threatening inflammatory mucocutaneous drug reaction (1– 3). SJS, also known as erythema multiforme major, lies on a continuum between erythema multiforme minor, characterized by targetoid cutaneous lesions encompassing less than 10% of the body surface area, and toxic epidermal necrolysis, characterized by widespread mucocutaneous involvement affecting 30%–100% of the skin surface (Table I) (4). The initial diagnosis of SJS is based on clinical presentation, but skin biopsies and direct immunofluorescence studies of the skin are essential to rule out other conditions such as autoimmune bullous disease (5,6).

Clinical manifestations SJS characteristically begins with vague upper respiratory tract symptoms lasting up to 2 weeks.

During this period, patients may complain of fever, sore throat, chills, headaches, and malaise (7). Persistent fever lasting longer than 4 weeks should raise suspicion of a concomitant infection, but studies have demonstrated that continued fever may occur in up to 85% of cases even in the absence of an associated infection (8). This is followed by the rapid onset of mucocutaneous lesions. Painful erosions of the mucous membranes are common and may affect any combination of the lip, oral cavity, conjunctiva, nasal cavity, urethra, vagina, gastrointestinal tract, and respiratory tract during the course of the illness (9–11). Involvement of mucous membranes is evident in approximately 90% of affected patients, and the absence of mucous membrane involvement should cast doubt on the diagnosis of SJS. Mucous membrane involvement can result in both short-term dysfunction and morbidity, as well as long-term complications due to fibrosis and strictures. The characteristic skin lesions seen in SJS are diffuse erythematous macules

Correspondence: Arash Kimyai-Asadi MD, DermSurgery Associates, 7515 Main, Suite 210, Houston, Texas 77030, USA. Fax: +1-713 791-9927. E-mail: [email protected] ISSN 0785-3890 print/ISSN 1365-2060 online # 2008 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS) DOI: 10.1080/07853890701753664

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Table I. Classification of Stevens-Johnson syndrome and toxic epidermal necrolysis (48,49).

Classification Stevens-Johnson syndrome Overlap Stevens-Johnson syndrome/Toxic epidermal necrolysis Toxic epidermal necrolysis

Body surface area involved

Key messages

N

v10% 10%–29% w30%

with purpuric, necrotic centers and overlying blistering (Figure 1). These cutaneous lesions often become confluent in some areas, and often demonstrate a positive Nikolsky sign, which is further detachment of the epidermis with slight lateral pressure. Targetoid lesions are typically present and are caused by epidermal necrosis in the center of lesions (4,12). As involvement progresses, affected portions of the skin slough, resulting in widespread superficial ulcers and loss of the epidermal barrier (13). The characteristic mucocutaneous lesions (Figure 1) tend to develop suddenly during the prodrome, and new lesions may continue to erupt for up to 4 weeks. Thereafter, the lesions reepithelialize. The mucocutaneous lesions seen in the prodromal period are often the predominant feature and may exist in the absence of skin lesions. Arriving at an accurate diagnosis can be challenging in cases that lack noticeable skin lesions (14). Thus, cultures of oral mucosa are indicated to help differentiate SJS from other causes of sore lesions in the oral mucosa including stomatitis, or virus-induced sloughing (15,16). For most patients, the most clinically significant elements of SJS are the sequelae of mucosal

N N

Early recognition and immediate withdrawal of offending agents are critical to minimizing debilitating or potentially life-threatening consequences of Stevens-Johnson syndrome (SJS). Pharmaceutical treatment of SJS remains controversial, although intravenous immunoglobulins (IVIg) are thought to hold promise for the management of SJS. A multidisciplinary approach, including prompt transfer to a burns unit in severe cases, is key to reducing the morbidity and mortality associated with SJS.

ulceration followed by scarring and stricture, resulting in significant deterioration of function of the affected organ systems. The organ most commonly affected in this manner is the eye, where corneal involvement affects the majority of patients and may result in corneal ulceration, perforation, and permanent sclerotic changes (17–19). Indeed, the majority of patients with SJS have long-term ocular complications. Less common and generally less debilitating ocular complications of SJS include anterior uveitis, iritis, keratitis, and conjunctivitis (17). Early consultation with and continued care by an ophthalmologist is critical in all patients with significant ocular involvement or injury (17–19). Urethral erosions are another common complication of SJS and may result in genitourinary strictures (15,20–22). In the acute setting, placement of a Foley catheter to maintain a patent urinary tract should be considered.

Figure 1. SJS in a patient on carbamazepine: Skin lesions demonstrating characteristic diffuse erythematous macules seen in SJS. The macules are typically targetoid with necrotic centers, and overlying flaccid blisters.

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A review of Stevens-Johnson syndrome Consultation with a urologist for evaluation and management of urethral ulceration and strictures is therefore warranted in patients with SJS (19–23). Gastrointestinal involvement has also been described, primarily affecting the esophagus, and often results in the development of esophageal webbing or stricture (24–26). In rare cases SJS may cause ulceration of the mucosa of other gastrointestinal organs such as the colon (27). Respiratory involvement in SJS has been reported in rare cases and is associated with poor prognosis (28,29). Pulmonary restriction may develop secondary to SJS-induced scarring of the pulmonary tract (30,31).

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SJS but in the presence of allopurinol, further strengthening the genetic association of the disorder (46). The increased frequency of HLA-B*1501 and HLA-B*1502 alleles amongst certain Asian populations has prompted health care officials in endemic regions to begin developing inexpensive tests to identify at-risk individuals prior to prescribing them allopurinol or carbamazepine (44). Furthermore, the presence of the HLA-DQB1*0601 allele places individuals at greater risk for the development of SJS with ocular complications and strengthens the notion of an underlying immunogenetic susceptibility to the development of SJS (46,47). These findings may aid clinicians in assigning appropriate therapy and yield improved benefit-to-harm ratios in patients with SJS.

Incidence SJS occurs at a rate of approximately 1–7 cases per million people per year (32–34). The risk of StevensJohnson syndrome remains low with any of its associated causes (32). SJS is fatal in approximately 5%–15% of cases (35). Both the incidence of the condition and the associated mortality rate appear to be elevated in immunocompromised patients with these risks correlating with worsening immune function (36,37). Chronic viral infections, such as Epstein Barr virus and Human Immunodeficiency Virus (HIV), may also increase the risk of SJS independently of the degree of immunosuppression (38–40). Autoimmune disorders, such as systemic lupus erythematosus, have also been reported to predispose to the development of SJS (1,41,42). A certain genetic predisposition may also confer increased risk of developing SJS on patients. In one study, the human leukocyte antigen (HLA) B1502 allele was found in 100% of SJS patients, placing individuals with that particular HLA allele at a 900 times greater risk of developing SJS than the general population (1). Given this genetic predisposition, certain ethnic groups in Asia have been identified as having an increased risk for SJS in comparison to the general population (43). This genetic susceptibility seems to have a strong association with specific drugs such as carbamazepine (44). Although HLAB*1502 confers greater risk of SJS on patients, this susceptibility is phenotype-specific. For instance, Caucasian patients with the HLA-B*1502 allele do not demonstrate the same susceptibility to SJS as Asian patients with the same genotype (44,45). Caucasian patients with the HLA-B*1502 genotype tolerate carbamazepine relatively well while 100% of the Han Chinese patients with the genotype developed SJS following carbamazepine administration (44,45). The presence of the HLA-B*1501 allele also confers an increased risk of developing

Diagnosis Considering an appropriate differential diagnosis in patients with mucocutaneous erosions can help eliminate misdiagnoses associated with these conditions (5,48). Among the most common disorders mistaken for SJS are staphylococcal scalded skin syndrome, toxic shock syndrome, exfoliative dermatitis, erythema multiforme, autoimmune bullous diseases, and chemical burns. Toxic shock syndrome and scalded skin syndrome, which are bacterial in nature, result in similar-appearing epidermolysis but are readily distinguishable from SJS following biopsy and immunofluorescence studies. Similarly, autoimmune bullous disease can be distinguished from SJS by the presence of IgA deposition in the former conditions (48). The absence of IgA deposition is characteristic of skin specimens of SJS patients (48,49). Graft-versus-host disease (GVHD) is another established cause of SJS independently of drug administration (50,51). Like SJS, graft-versushost disease is mediated by cytotoxic T cells that result in epidermal necrosis and keratinolysis (52– 54). Furthermore, the clinical and histological appearance of GVHD can mimic SJS making distinguishing the two disorders challenging (54). For instance, the blister fluid of both conditions demonstrate the presence of CD8+ T cells, further complicating the ability of clinicians to distinguish the two (55). Histologically, both GVHD and SJS result in apoptosis of epidermal Langerhans cells (LCs) and often show decreased numbers of such cells in the dermis (56). Because of the difficulty in distinguishing the two disorders clinically and histologically, conducting a thorough history and physical examination as well as early dermatologic consultation remain the cornerstone of diagnosis in instances where both SJS and GVHD are part of the

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differential diagnosis (6,54). Incidentally, Lyme disease also presents with targetoid lesions. However, unlike SJS, which is associated with numerous targetoid lesions, Lyme disease typically presents with a single or small number of targetoid lesions that surround a central dusky area representing a tick bite site (57,58). Furthermore, mucosal involvement is not present in Lyme disease, and patients with SJS are generally ill and have a very rapid onset of lesions as compared to patients with erythema chronicum migrans. The diagnosis of SJS is generally made on clinical grounds based on the presence of classic mucocutaneous lesions. In most cases confirmation of the diagnosis should be sought by skin biopsies, which typically reveal vacuolization of basal layer keratinocytes associated with lymphocytes along the dermal-epidermal junction and necrotic spinous layer keratinocytes (49,59–61). The typical histopathological appearance of SJS is characterized by apoptosis and necrosis of keratinocytes along with dermoepidermal detachment and lymphocytic infiltration of perivascular regions (4,6). Intraepidermal vesicles and papillary dermal edema may be noted in more papular lesions. In severe cases, subepidermal blistering associated with full-thickness epidermal necrosis may be present, but this is generally considered the hallmark of toxic epidermal necrolysis. To distinguish this condition from autoimmune blistering disorders, biopsies should be submitted both for routine histopathology as well as for direct immunofluorescence studies.

Etiology Although a variety of etiologies, such as infections and underlying malignancies, have been implicated as potential causes of SJS, drugs remain the predominant inciting agent (Table II). The most commonly implicated drugs are sulfa derivatives, nonsteroidal anti-inflammatory agents, penicillinrelated and cephalosporin antibiotics, antiepileptics,

allopurinol, and terbinafine. There also appears to be an increased risk of developing SJS with higher dosages of offending medications (62,63). Although they have been implicated in rare cases, overall, vaccine administration and chemical exposure are rarely associated with SJS (64–66). Cyclooxygenase-2 inhibitors have also been implicated as potential underlying sources of the disorder (67). Recreational drugs such as cocaine (68) as well as over-the-counter and alternative medicines have also recently been implicated as causes of SJS (69). According to recent studies, as many as 64% of individuals diagnosed with SJS have been exposed to drugs suggesting that in up to one-third of cases no specific etiology has been identified (70). Although medications are the most common causative agents in adults, similar trends do not apply in the pediatric population (5). In fact, SJS in pediatric patients is more commonly triggered by infectious organisms than adverse drug reaction (5). An awareness of this distinction is critical to arriving at an accurate diagnosis and treatment of the condition. Underlying infections are the second most common cause of SJS. The most commonly associated infectious agents are listed in Table II. The most common implicated organism is Mycoplasma pneumoniae which is oftentimes seen in children and may be the reason for widespread cases of SJS during Mycoplasma epidemics (71,72). Although other infectious etiologies have been identified as causative agents for the condition, most remain uncommon with the exception of herpes simplex virus which has been implicated in acute as well as recurrent bouts of SJS in adults and children (71,73,74). Moreover, a number of underlying malignancies, such as squamous cell carcinoma of the lung, Hodgkin’s lymphoma, and certain forms of leukemia have been associated with SJS (75–77). Pathophysiology The exact pathophysiologic mechanism of SJS remains unknown. Various theories have implicated

Table II. Etiologies of Stevens-Johnson syndrome. Etiologic agent Viral Bacterial Fungal Protozoal Drugs

Most frequently described AIDS, herpes simplex virus, Epstein-Barr, influenza, coxsackie, lymphogranuloma venereum, and variola Mycoplasma pneumoniae, typhoid, tularemia, diphtheria, and group A streptococci Dermatophytosis, histoplasmosis, and coccidiomycosis Trichomoniasis, plasmodium Sulfas, nonsteroidal anti-inflammatory drugs (NSAIDs), antiepileptics, barbiturates, allopurinol, tetracyclines, antiparasiticsa

a Sulfa drugs (96,107,120), antiepileptics (97,102,123,124,130), allopurinol (103,130), tetracyclines (104) are more common in the setting of a compromised immune system (19,20,25,134), antiparasitic and antibacterial drugs (23,104,105), antiviral agents (48,119,120), antifungal agents (24), NSAIDS (31,46,121,122), infectious etiologies (4,108,109,117,118).

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A review of Stevens-Johnson syndrome both immunological and nonimmunological mechanisms, with the prevailing evidence suggesting primary involvement of the immunologic response (78), in particular those mediated by memory cytotoxic T cells (79). Although it was originally classified as a type IV, delayed hypersensitivity reaction, it now appears that the immunological mechanisms governing the SJS reaction are initiated by the Fas antigen, a cell surface molecule that can mediate apoptosis (80,81). Activation of the Fas signaling cascade leads to widespread keratinocyte apoptosis and subsequent epithelial necrosis. Early treatment of SJS via intravenous immunoglobulins (IVIg) blocks the activation of the Fas pathway, thus underscoring the potential effectiveness of IVIg in treating the disorder (35,82,83). Recent studies have also linked perforin, a pore-making monomeric granule released from natural killer T-lymphocytes in the development of SJS. Perforin is believed to initiate the keratinolysis seen early in the development of SJS (84). Some evidence also exists linking IgE-mediated mechanisms and mast cell activation contributing to SJS (85). Genetic factors may play a role in the development of SJS. It has been postulated that patients with slow intrinsic acetylation rates and those taking medications such as azoles, protease inhibitors, serotoninspecific reuptake inhibitors, and quinolones are at increased risk of developing SJS (1,86–88). Slow acetylation may indeed be a factor in the development of a number of adverse cutaneous drug reactions (89), as the reduced rate of acetylation causes the accumulation of reactive metabolites that induce cell-mediated cytotoxic reactions directed against the epidermis, resulting in keratinocyte apoptosis (90).

Treatment SJS is a serious systemic disorder with the potential for severe morbidity and mortality. In approximately 5%–15% of cases SJS is fatal (35,39). In order to determine a patient’s risk of death with SJS, clinicians are encouraged to use the SCORTEN (TEN-specific severity of illness score) scale which employs important prognostic indicators including heart rate, age, and renal function (91,92) (Table III). Assessing the SCORTEN score requires giving the patient one point for each positive variable his condition fulfills. The total points are tallied, with increased scores correlated with poorer prognosis. Effective management of SJS begins with prompt recognition of the entity, combined with attention to each of the major organs that may be affected, as well as potential comorbidities. Since medications

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Table III. SCORTEN scale (91,92). One point is added for each positive variable. A patient’s mortality can be predicted by the total number of points according to the following breakdown: 0–1 points53.2% mortality; 2 points512.1% mortality; 3 points535.3% mortality; 4–5 points58.3% mortality; w5 points590% mortality. Variable Age Malignancy Heart rate Body surface area involved at day 1 Serum blood urea nitrogen (BUN) Serum bicarbonate Serum glucose

Value w40 year Present w120 per minute w10% w10 mg/dL v20 mg/dL w14 mg/dL

are the most common cause of SJS, a thorough drug history must be obtained, and all potential offending agents must be immediately discontinued (32,39). Indeed, immediate cessation of involved medications appears to improve the prognosis (93). Comprehensive SJS treatment requires a skilled, collaborative, multidisciplinary approach that addresses the highly complex, systemic response to the condition. A multispecialty team may also assist in subsequent postdischarge management including psychosocial issues that may arise from SJS-induced disfigurations or scarring. The management of milder cases of SJS may occur in an inpatient ward with the same fundamental therapeutic protocol used for burns: warming of the environment, minimizing transepidermal water loss, treatment of electrolyte imbalances, administration of high-calorie nutrition and intravenous fluids to prevent dehydration, and prevention of sepsis (38,39,94– 96). For patients with extensive cutaneous involvement, prompt referral to a burns unit has been shown to reduce the risk of infection, mortality, and the length of hospitalization (94,96–101). This is particularly true for SJS caused by drugs with short half-lives, which represent a positive prognostic factor for SJS (94). Patients must be counseled regarding strict future avoidance of agents responsible for the outbreak as well as chemically similar compounds. Given the suspected hereditary association with SJS, first-degree relatives should also be encouraged to avoid similar chemical compounds. Targeted nursing care including adequate maintenance of topical management reduces associated morbidity and allows a more rapid reepithelialization of skin lesions and the prevention of scarring, synechia formation, and infection (39,100). Skin erosions should be covered with moisture-retentive ointments and/or topical antibiotics to improve barrier function and to prevent bacterial infection. Given the involvement of the lips and oral mucosa in

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many patients with SJS, adequate emphasis on alleviating pain associated with lesions in the mouth is an integral part of treating the disorder. Application of petroleum jelly and sterile saline compresses can promote rapid reepithelialization of the lips. The use of viscous lidocaine on the oral mucosa in combination with diphenhydramine or sodium bicarbonate mouthwashes can dramatically relieve pain associated with friable mucocutaneous ulcerations and prevent the onset of odynophagia (102–104). For patients with ocular involvement, daily erythromycin eye drops are recommended to prevent bacterial infections, and corticosteroid eye drops are administered to reduce inflammation (4). Continued ophthalmologic care is recommended even after recovery in order to monitor and minimize irreversible ocular complications including visual loss. Involvement of other organs is addressed with appropriate supportive care as well as treatment of any strictures, adhesions, or scarring that may complicate the course of the disease. Respiratory involvement may require prompt intubation and ventilatory support (28,29). The use of medications to treat SJS has met with intense debate over the years. Treatment with corticosteroids, while effective in most other acute inflammatory disorders, is controversial (105–110). Furthermore, numerous other anti-inflammatory, immunosuppressive, and immunomodulatory agents, such as cyclosporin, cyclophosphamide, thalidomide, and intravenous immunoglobulins (IVIg), have been administered as possible means to arrest underlying immunological mechanisms promoting SJS (39,111,112). However, the efficacy of these agents in the treatment of SJS has not been demonstrated by any controlled clinical trial. In the absence of strong evidence, none of these regimens can be definitively proposed as a treatment of choice. This notwithstanding, IVIg administered early after the onset of mucocutaneous lesions is thought to hold the most promise for improvement in survival and a reduction in longterm morbidity (82,83,113). The dose of IVIg administered varies, but typically is 1–3 g/kg/day for 3–5 days, with a mean total dose of 2.7 g/kg divided over 1–5 days (23,70,114,115). Studies have demonstrated that IVIg arrests Fas-mediated keratinolysis in vitro, which provides a pathophysiologic explanation of why it may improve SJS through disruption of Fas-induced keratinocyte apoptosis (83,109). Moreover, intravenous immunoglobulins have yielded promising results in controlled studies involving children (111) as well as adults (115). For example, a recent retrospective

analysis reported a 100% survival rate and complete skin healing in 12 patients with SJS after treatment with IVIg (115). However, the absence of large or controlled trials raises questions regarding the efficacy of IVIg, particularly given the high cost of this treatment (116). In the absence of clear-cut benefits, potential risks of IVIg should be reviewed with the patient prior to treatment. Sepsis is a major source of mortality in SJS patients. However, prophylactic antibiotics are not recommended in the treatment of acute SJS except when the etiologic agent is identified as an infectious agent. For example, although supportive therapy was once considered treatment of choice for Mycoplasma-induced SJS, antibiotic therapy is now typically administered to treat the infection (72). The presence of an opportunistic infection due to HIV or immunosuppression represents a poor prognosis in the evolution of SJS and toxic epidermal necrolysis (TEN) (36,37,40). Although prophylactic antibiotics are not recommended, the use of skin cultures on the first day and every 48 hours thereafter is recommended as a means of monitoring possible bacterial growth. Topical antibiotic treatment should begin if there is an increased number of bacteria cultured from the skin with selection of a single strain, a sudden drop in temperature, and/or deterioration in the patient’s condition. Prompt and uninterrupted enteral nutrition reduces the incidence of stress ulcers and bacterial translocation, and allows earlier discontinuation of intravenous lines (39). Finally, treating the patient’s existing health concerns is paramount. For example, regardless of whether SJS is suspected to be secondary to a drug reaction, prophylactic use of anticoagulants maybe indicated due to the risk of thromboembolisminduced morbidity and mortality (1). Furthermore, based on the severity of the disease, analgesics along with supportive emotional and psychological care should be provided as needed. Conclusions SJS is a rare but serious adverse cutaneous reaction most commonly due to medications and infectious agents. Prompt recognition is critical for the initiation of appropriate care. The mainstay of treatment remains addressing the causative agent as well as supportive care for the mucocutaneous ulcerations. This requires a multidisciplinary approach to all organ systems that may be affected by this disease. In severe cases, prompt transfer to a burns unit is necessary in order to decrease both morbidity and mortality. While systemic corticosteroids should be

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A review of Stevens-Johnson syndrome avoided in the management of SJS, IVIg should be considered early in the disease, even though its efficacy has not been definitively established. Patients at risk of or those previously afflicted by SJS should receive counseling on the importance of completely avoiding responsible agents or similar compounds. Furthermore, physicians and health care workers are encouraged to improve documentation of offending agents in patient charts in order to minimize the risk of repeat outbreaks of the disease.

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