Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially life threatening, diseases characterized by widespread epidermal necrosis, and are predominantly medication-induced. Unfortunately, though they are often associated with long-term debilitating sequelae, there are currently no efficacious pharmaceutical interventions proven through large clinical trials. It has been well established that the epidermal damage in these diseases is due to keratinocyte apoptosis. Although drug-specific T cells are implicated in this process, our understanding of the immunopathology is far from complete. The scenario suggested by today's literature points towards drug-specific CD8+ cytotoxic T cells utilizing perforin/granzyme B trigger keratinocyte apoptosis. Subsequently, there may be an expansion of apoptosis involving the interaction of either membrane-bound or soluble Fas ligand (sFasL) with its receptor Fas. The cellular source of sFasL remains controversial, with both peripheral lymphocytes and keratinocytes themselves as potential candidates. Cytokines produced by T lymphocytes, macrophages or keratinocytes may participate by activating keratinocytes and enhancing their expression of Fas and FasL, or by promoting the skin recruitment of lymphocytes by upregulating adhesion molecules. A better understanding of the underlying immunological mechanisms is required to identify appropriate therapeutic interventions. Finally, clinicians must remain vigilant about drug hypersensitivity to prevent SJS/TEN.     

Stevens-Johnson syndrome and toxic epidermal necrolysis in children

The Stevens-Johnson syndrome (SJS) and the toxic epidermal necrolysis (TEN) are clinical conditions manifesting as adverse cutaneous reaction to drugs in majority of cases, constituting the same clinical spectrum, differing only in the severity of epidermolysis; both conditions are distinguished by their severity and extensiveness of skin lesions; it can also involve mucous membranes of eyes, respiratory, digestive and urogenital tracts. Two per 1,000,000 are affected annually, among them approximately 20% are children and both of them are considered as potentially fatal medical emergency conditions. Even though the condition was described 89 years ago, until now the exact pathophysiology has not been completely explained. An immune-mediated mechanism has been implicated in its origin, which involves cytotoxic lymphocytes, cytokines, Fas-ligand in keratinocyte apoptosis; genetic makers also has been identified in some racial groups (HLA-B*1520, HLA-B*5801) in relationship with specific susceptibility to certain drugs such as carbamazepine, allopurinol. In children there are no uniform criteria for classification of the skin lesions, neither for the treatment, however recently the authors describe better response of the patients with use intravenous immunoglobulin (IGIV).     

Toxic epidermal necrolysis

Toxic epidermal necrolysis is the prototype of a proapoptotic disease characterized by system CD95 dysrregulation. Drugs constitute the main antigenic triggers. Hystopatologically it is characterized by epidermis detachment and necrosis with apoptotic keratinocytes. Clinical presentation includes erithematous-ampullous lesions in the skin and mucous membranes. It is associated with serious complications such as severe sepsis and septic shock. The management in the intensive care unit includes support treatment and specific treatment with immunoglobulins that alter disease course. Recombinant activated Factor VII is effective to control the associated microvascular haemorraghe.     

The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome has long been considered to resemble erythema multiforme with mucosal involvement, but is now thought to form a single disease entity with toxic epidermal necrolysis. Although Stevens-Johnson syndrome is less severe, etiology, genetic susceptibility and pathomechanism are the same for Stevens-Johnson syndrome/toxic epidermal necrolysis. The condition is mainly caused by drugs, but also by infections and probably other risk factors not yet identified. Identification of the cause is important for the individual patient and in cases of drug-induced disease withdrawal of the inducing drug(s) has an impact on the patient's prognosis. If an infectious cause is suspected, adequate anti-infective treatment is needed. Besides this, supportive management is crucial to improve the patient's state, probably more than specific immunomodulating treatments. Despite all of the therapeutic efforts, mortality is high and increases with disease severity, patients' age and underlying medical conditions. Survivors may suffer from long-term sequelae such as strictures of mucous membranes including severe eye problems.     

Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications

Introduction: Stevens-Johnson syndrome (SJS) and its severe phenotype, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucosa. Approximately 50% of SJS/TEN patients diagnosed by dermatologists and in burn units suffer from severe ocular complications (SOC) in the acute stage.

Areas covered: Earlier studies on patients with SJS/TEN with SOC identified cold medicines including multi-ingredient cold medications and non-steroidal anti-inflammatory drugs as the main eliciting drugs. HLA analyzes showed that genetic predisposition might play a role in the response to these drugs. Our analysis of the association between HLA genotypes and cold medicine-related SJS/TEN (CM-SJS/TEN) with SOC revealed that certain HLA genotypes play a role in the development of SJS/TEN with SOC. Genetic predisposition and other factors contributing to the elicitation of CM-SJS/TEN with SOC and the management of patients in the acute and chronic stage of the disease are discussed.

Expert opinion: The main sequelae of SJS/TEN are ocular sequelae with visual disturbance. SJS/TEN with SOC needs ophthalmic treatment in addition to systemic treatment from the onset time to reduce the ophthalmic sequelae. In addition, HLA examination and public awareness of SJS/TEN with SOC due to cold medicine use might contribute to preventing visual disturbance due to SJS/TEN.

Abbreviations: SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis; SOC: severe ocular complications     

Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal necrolysis.

OBJECTIVE: To review the current pathophysiologic mechanisms and recent therapeutic trends in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). DATA SOURCES: A MEDLINE search for SJS and TEN in combination with Fas, Fas ligand (FasL), cytotoxic T cells, intravenous immunoglobulin, and cyclosporine for articles published in English during 1966 to 2006. STUDY SELECTION: Information was derived from original research articles and reviews published in peer-reviewed journals. RESULTS: The hallmark of SJS and TEN is epidermal cell apoptosis, which may be mediated through keratinocyte Fas-FasL interaction or through cytotoxic T-cell release of perforin and granzyme B. Whereas systemic corticosteroid therapy showed contradictory results, intravenous immunoglobulin (IVIG) and cyclosporine have shown promising outcomes. IVIG contains anti-Fas antibodies that can abrogate apoptosis when preincubated with keratinocytes. Most studies on IVIG in SJS and TEN reported improvement in arresting disease progression and reduction in time to skin healing. Because of variations among studies, the findings cannot be optimally compared. In general, mortality varied from 0% to 12% in studies that supported the use of IVIG and 25% to 41.7% in those that did not demonstrate a beneficial effect. Cyclosporine inhibits CD8 activation and thus may reduce epidermal destruction. Relatively few case reports and 1 case series have been published regarding the use of cyclosporine in SJS and TEN. In general, cyclosporine was associated with a significant improvement in time to disease arrest and to complete reepithelization, with no reported fatalities. CONCLUSIONS: Both IVIG and cyclosporine have been associated with enhanced healing and better survival through inhibition of apoptosis. Multicenter, randomized, placebo-controlled trials using a standardized design are needed to validate these findings.     

Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature.

OBJECTIVE: To perform a comprehensive review of Stevens-Johnson syndrome and toxic epidermal necrolysis. DATA SOURCES: A MEDLINE search was performed for the years 1975 to 2003 using the keywords Stevens-Johnson syndrome and toxic epidermal necrolysis to identify relevant articles published in English in peer-reviewed journals. STUDY SELECTION: All clinical studies that reported on 4 or more patients, review articles, and experimental studies that concerned disease mechanisms were selected and further analyzed. Clinical reports that included fewer than 4 patients were selected only if they were believed to carry a significant message about disease mechanism or therapy. RESULTS: Stevens-Johnson syndrome and toxic epidermal necrolysis seem to be variants of the same disease with differing severities. A widely accepted consensus regarding diagnostic criteria and therapy does not exist at present. Despite the recent experimental studies, the pathogenic mechanisms of these diseases remain unknown. Although progress in survival through early hospitalization in specialized burn units has been made, the prevalence of life-long disability from the ocular morbidity of Stevens-Johnson syndrome and toxic epidermal necrolysis has remained unchanged for the past 35 years. Further progress depends on modification of the acute phase of the disease rather than continuation of supportive care. The available published evidence indicates that a principal problem in the pathogenesis is immunologic and that immunomodulatory intervention with short-term, high-dose intravenous steroids or intravenous immunoglobulin holds the most promise for effective change in survival and long-term morbidity. CONCLUSIONS: The results of this review call for a widely accepted consensus on diagnostic criteria for Stevens-Johnson and toxic epidermal necrolysis and multicenter collaboration in experimental studies and clinical trials that investigate disease mechanisms and novel therapeutic interventions, respectively.     

Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells

BACKGROUND: Toxic epidermal necrolysis (TEN) is a very rare but extremely severe drug reaction characterized by widespread apoptosis of epidermis with extensive blisters. We previously found drug-specific cytotoxic CD8 T lymphocytes in the blisters of a single patient. OBJECTIVE: To confirm the role of drug specific cytotoxic lymphocytes in a larger series, to test the cytotoxicity on keratinocytes, and to look for cross-reactivity between chemically related drugs. METHODS: The phenotype of lymphocytes present in the blister fluids of 6 patients with TEN was analyzed by flow cytometry. Cytotoxic functions were tested by chromium release assay on a variety of target cells (autologous or MHC class I-matched EBV-transformed lymphocytes, autologous keratinocytes) after nonspecific (CD3 monoclonal antibody) or specific (suspected and potentially cross-reactive drugs) activation. RESULTS: Blister lymphocytes were CD8 + HLA-DR + CLA + CD56 + . In all 6 cases, they were cytotoxic after nonspecific activation. A drug-specific cytotoxicity was observed in 4 cases (3 related to cotrimoxazole and 1 to carbamazepine) toward lymphocytes. Blister cells also killed IFN-gamma-activated autologous keratinocytes in the presence of drug in the 2 patients tested. Blister cells showed a strong immunoreactivity for granzyme B, and cytotoxicity was abolished by EGTA, but not by anti-Fas/CD95, suggesting perforin/granzyme-mediated killing. By using several sulfonamides for testing the specificity of the drug T-cell receptor interaction, we observed cross-reactivity only between 4 structurally closely related medications. CONCLUSION: These results strongly suggest that drug-specific, MHC class I-restricted, perforin/granzyme-mediated cytotoxicity probably has a primary role in TEN.     

T-cell receptor and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: understanding a hypersensitivity reaction

Ample evidence exists to support the view that drug hypersensitivity is mediated by adaptive immunity, which involves MHC-restricted drug presentation, activation and clonal expansion of T cells. The specific MHC molecules implicated in hypersensitivity have been identified; for example, HLA-B*5701 in abacavir-induced drug hypersensitivity and HLA-B*1502 in carbamazepine-induced Stevens-Johnson syndrome. However, little is known about the role of drug-specific T cells and their T-cell receptors (TCRs) in the pathogenesis of drug hypersensitivity. Using the combination of a strong HLA-B*1502 predisposition in carbamazepine-induced Stevens-Johnson syndrome and applying global analysis of the TCR repertoire, restricted and common TCR usage in the development of severe drug hypersensitivity have recently been documented. This article reviews recent advances in the understanding of the pathogenic role of drug-specific T cells and their TCRs in the development of drug hypersensitivity and provides an analysis of their potential clinical implications.     

Ocular manifestations and complications of Stevens-Johnson syndrome and toxic epidermal necrolysis: an Asian series

BACKGROUND: To describe the acute and late ocular manifestations and complications in toxic epidermal necrosis (TEN) and Stevens-Johnson syndrome (SJS), and identify predictors for development of late complications. METHODS: Cases of TEN and SJS during a 9-year period were included. Patients with ocular involvement were reviewed for acute ocular complications. Patients with a minimum 6 months follow-up were reviewed for late complications. Records were reviewed for their demographics, etiology, and severity of ocular involvement. RESULTS: There were 117 patients with a mean age of 52.2 +/- 18.6 years. Eighty-one of these (69%) had acute ocular involvement. This was mild in 40%, moderate in 25% and severe in 4%. Adverse drug reactions were the predominant cause. Patients with thrombocytopenia had more severe acute ocular involvement. Forty-four patients had a minimum 6 months of follow-up and half developed late complications. Severe dry eyes and trichiatic lashes were the commonest late complications. Patients treated with topical antibiotic were more likely to have late complications, particularly dry eyes. There was no difference in the severity of acute eye involvement or late complications when SJS and TEN patients were compared. The severity of the acute ocular disease and abnormal laboratory tests were not found to be the significant risk factors of late complications. CONCLUSIONS: Ocular involvement is common in SJS and TEN and can be severe and blinding. The severity of acute ocular complications does not predict late complications. The diagnosis of TEN does not imply a more severe ocular involvement or increased frequency of late ocular complications compared with SJS. Care should be taken even in mild cases. Appropriate intervention during acute ocular disease may prevent late complications.     

Toxic epidermal necrolysis due to vancomycin.

Toxic epidermal necrolysis due to vancomycin is reported in a patient with human immunodeficiency virus infection. The same patient had anaphylaxis to cloxacillin but tolerated other penicillin derivatives. These reactions were documented using in vivo and in vitro tests. The role of human immunodeficiency virus infection in the pathogenesis of these reactions is discussed.     

Toxic epidermal necrolysis in systemic lupus erythematosus

Toxic epidermal necrolysis (TEN) is an acute, rapidly evolving mucocutaneous reaction with a high mortality rate characterized by extensive painful cutaneous and mucosal exfoliation and systemic involvement that is frequently associated with medication use. The treatment of this condition is controversial. Systemic lupus erythematosus (SLE) is a generalized autoimmune disease of unknown etiology characterized by the production of autoantibodies to self antigens. Several case reports in the literature have demonstrated an association between SLE and TEN, and it has been postulated that lupus-associated TEN may exist. In this review, we will explore the association of SLE and TEN, and its diagnosis and treatment.     

Intravenous ulinastatin therapy for Stevens-Johnson syndrome and toxic epidermal necrolysis in pediatric patients. Three case reports

BACKGROUND: More effective therapy is needed for the treatment of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The clinical efficacy of intravenous ulinastatin therapy was investigated in 3 Japanese pediatric patients with SJS or TEN. METHODS: Ulinastatin was given to 1 pediatric SJS patient and 2 pediatric TEN patients within 7 days (patient 1; SJS), 6 days (patient 2; TEN), or 4 days (patient 3; TEN) after the onset of the skin rash. Ulinastatin was administered intravenously at a dose of 7,500 U/kg/day (maximum dose: 300,000 U/day). No corticosteroids were given. After the skin lesions resolved, the ulinastatin dose was reduced to between 2,500 and 5,000 U/kg/day as maintenance therapy and then the drug was withdrawn. RESULTS: Erythema, fatigue, and fever improved within 12-36 h of starting the ulinastatin infusion, and the skin lesions resolved completely after 4-7 days of ulinastatin therapy. None of the patients had cutaneous or ocular sequelae. No patient developed secondary infection or relapse and ulinastatin therapy caused no side effects. CONCLUSION: Ulinastatin dramatically reduced the febrile period with no adverse effects and was very safe in this study. Ulinastatin appears to be a useful and effective therapy for controlling SJS and TEN without sequelae.