Treatment of erythema multiforme, Stevens–Johnson Syndrome, and toxic epidermal necrolysis

The "erythema multiforme disease spectrum" comprises four distinct, severe, clinical subvariants: (1) bullous erythema multiforme (bullous-EM), (2) Stevens–Johnson syndrome (SJS), (3) SJS–toxic epidermal necrolysis (TEN)-overlap syndrome, and (4) TEN. These diseases are closely related to severe mucocutaneous intolerance reactions that are mostly elicited by drugs/drug metabolites and associated with a high mortality rate. Old age and area of detached skin negatively influence the course of disease, and early withdrawal of causative drugs with short half-life is a positive prognostic factor. Therapeutic management represents a multidisciplinary challenge for colleagues from various specialities including specialized nurses and usually can be performed at a dermatologic ward unless technical equipment of an intensive care unit is needed. Topical therapy with biologic and (semi-)synthetic dressings is aimed at early re-epithelialization and the prevention of scarring, synechia formation, and infection. Systemic treatment includes antibiotics, fluid and electrolyte replacement, protein preparations and blood products, etc. Various anti-inflammatory and immunosuppressive treatment regimens with corticosteroids, cyclosporine A, cyclophosphamide, plasmapheresis have been considered to halt ongoing immunologic pathomechanisms, and some of these have shown significant efficacy. However, because we lack formal clinical trials, none of these regimens can be definitively proposed as a therapy of choice in any of the severe clinical variants of the EM spectrum.     

Erythema multiforme,Stevens‐Johnson syndrome/toxic epidermal necrolysis – diagnosis and treatment

Prior to the first international consensus classification published in 1993, the clinical distinction between erythema multiforme (EM), Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) had been subject to uncertainty and controversy for more than a century. Based on this classification, the three conditions are defined by the morphology of the individual lesions and their pattern of distribution. Etiopathogenetically, the majority of EM cases is caused by infections (primarily herpes simplex virus and Mycoplasma pneumoniae), whereas SJS/TEN are predominantly triggered by drugs. The SCORTEN (score of toxic epidermal necrolysis) can and should be used to assess disease prognosis in patients with SJS/TEN. While supportive treatment is generally considered sufficient for EM, there is still uncertainty as to the type of systemic therapy required for SJS/TEN. Given the lack of high‐quality therapeutic trials and (in some cases) conflicting results, it is currently impossible to issue definitive recommendations for any given immunomodulatory therapy. While there is always a trade‐off between rapid onset of treatment‐induced immunosuppression and an uptick in infection risk, there has been increasing evidence that cyclosporine in particular may be able to halt disease progression (i.e. skin detachment) and lower mortality rates. Assistance in diagnosis and management of the aforementioned conditions may be obtained from the Center for the Documentation of Severe Skin Reactions (dZh) at the Department of Dermatology, University Medical Center, Freiburg, Germany.     

Erythema multiforme,Stevens–Johnson syndrome and toxic epidermal necrolysis: Frozen‐section diagnosis

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) may be fatal. Although classified by body surface area skin detachment, initial stages of both may present with erythema multiforme (EM)‐like lesions. To diagnose and predict disease activity adequately as early as possible for patients revealing EM‐like lesions, we performed frozen‐section diagnosis. Thirty‐five patients clinically diagnosed as EM, SJS or TEN were biopsied to diagnose and predict disease progression within the initial‐visit day. Half of a histological section taken from a lesion was snap‐frozen and immediately cryostat‐sectioned, acetone‐fixed and stained with hematoxylin–eosin. Specimens were examined with light microscopy for presence of epidermal necrosis. A section from unaffected sites was also examined for 11 patients. Specimens were examined with light microscopy for presence of graft‐versus‐host reaction (GVHR)‐like findings: apoptotic keratinocytes and satellite cell necrosis. Epidermal necrosis was seen in nine patients. Initial diagnosis of the nine was one of overlap SJS‐TEN, four of SJS and four of EM, and final diagnosis of those was one of TEN, one of overlap SJS–TEN, four of SJS and three of EM. Dissociation between initial and final diagnosis was seen in three cases. GVHR‐like findings in the epidermis were observed in two patients finally diagnosed as overlap SJS–TEN and TEN. Frozen sections are useful not only to make a diagnosis of erythema multiforme but to assess a potential to exhibit more aggressive clinical behaviors (SJS or TEN).     

Clinical risk management of Stevens–Johnson syndrome/toxic epidermal necrolysis spectrum

Clinical risk management concedes that risk is inherent to all health-care processes. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but potentially life-threatening reactions to medications. Risk management should be considered prior to starting, during, and after therapy. Prior to starting therapy, risks that need to be assessed include any specific patient groups that may be at greater risk for the development of SJS/TEN. Gene testing is in place for Chinese and Thai patients who are going to be exposed to carbamazepine. During therapy, it is important to recognize SJS/TEN as a possible adverse drug reaction. Diagnostic criteria have changed, and more data exist on drugs with an increased risk. Although there is no standardized treatment for all patients with SJS/TEN, options that have been used include cyclosporine, corticosteroids, and intravenous immunoglobulin. Standards of care are usually defined locally, but new treatments, such as amniotic membrane support for ocular damage, may need to be considered. Good communication skills are needed to allow practitioners to show empathy and to provide disclosure. Risk management after a reaction includes skills in acknowledging bad outcomes or error; freedom to say "sorry" as defined by "apology laws," and knowing the rights provided by "Quality Assurance Conferences," where the information discussed is protected. In other words, the patient is best supported after an event like SJS/TEN if the practitioner is knowledgeable about optimal care standards and their legal rights and obligations.     

Clinical manifestations and outcomes in 17 cases of Stevens–Johnson syndrome and toxic epidermal necrolysis

The clinical features and outcomes of 17 patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) were retrospectively reviewed. There were 11 males and six females with an average age of 61.5 years. Ten patients with SJS (seven males, three females) and seven patients with TEN (four males, three females) were identified. Antibiotics, mainly beta-lactams, were the most common cause of SJS/TEN in this series. The mean skin loss in TEN was 45.7% total body surface area in contrast to the lesser skin loss (< 10%) observed in three patients with SJS. Complications included septicaemia, pneumonia and multi-organ failure, mainly in the TEN group. Two patients died from TEN-related complications and one patient with SJS died from unrelated causes. Ocular involvement and skin pigmentary changes represented the most significant long-term sequelae.     

Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens—Johnson syndrome and toxic epidermal necrolysis

Summary The clinical and histopathological classification of erythema exudativum multiforme major (EEMM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are difficult, due to the lack of clear-cut criteria. Based on a new clinical classification, 149 of 219 (68%) histopathological specimens, from a total of 534 patients with EEMM. SJS and TEN, have been reviewed. A comparison was made with the clinical picture, and any past history of infection or drug intake. All patients had been included in the German Registry of Severe Skin Reactions between April 1990 and December 1993. No differences could be found between the biopsies examined and the total number of histopathological specimens, concerning clinical diagnosis, gender and age. Sections from 28 of 149 specimens were not diagnostic or were too old to be properly evaluated. In nine cases, other diagnoses were proposed. One hundred and eleven of the histological slides with the diagnosis of EEMM (n= 16), SJS (n=34) and TEN (n=61), were classified as epidermal type of erythema multiforme. In these 111 slides, necrotic keratinocytes could be found, ranging from individual cells to confluent epidermal necrosis. The epidermo-dermal junction showed changes ranging from vacuolar alteration up to subepidermal blisters. The dermal infiltrate was superficial and mostly perivascular. It was sparse in SJS and TEN, and more pronounced in EEMM. Oedema in the papillary dermis was evident occasionally in all clinical groups. In 59 of 111 cases (53%), at least one eosinophil was present in the dermis. In 11 of 111 (10%), more than 10 eosinophils per field could be seen. Eosinophils were less common in the patients with the most severe forms of TEN, in whom there was detachment of more than 30% of the skin surface area. No differences in the history for drug intake, or for infection with Mycoplasma pneumoniae, herpes simplex and other organisms, could be detected between patients with or without eosinophils in their skin sections. This dermatopathological study of patients with EEMM. SJS and TEN indicates that the epidermal type of erythema multiforme is the pathological correlate for these diseases.     

Efficacy and safety of cyclosporine in Stevens–Johnson syndrome and toxic epidermal necrolysis

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life threatening cutaneous reactions that are most commonly caused by exposure to medications. This review assesses the efficacy and safety of cyclosporine therapy for SJS, TEN, and SJS/TEN overlap. A literature review was conducted in PubMed using the MeSH terms TEN, SJS, and cyclosporine. Five case series and one meta‐analysis were analyzed. From review of the existing literature, cyclosporine appears to not only have a mortality benefit in the treatment of SJS/TEN, but also a relatively safe side effect profile.     

Combination therapy of intravenous immunoglobulin and corticosteroid in the treatment of toxic epidermal necrolysis and Stevens–Johnson syndrome: a retrospective comparative study in China

Background Toxic epidermal necrolysis (TEN) and Stevens–Johnson Syndrome (SJS) are drug‐induced diseases with no well‐established treatments. The application of corticosteroid therapy is controversial. Intravenous immunoglobulin (IVIG) therapy is emerging as a promising new method for the treatment of these two diseases. The efficacy of combination therapy of IVIG and corticosteroid in the treatment of TEN/SJS has seldom been reported. Methods Sixty‐five consecutive patients with either TEN or SJS, admitted over a 14‐year period from January 1993 to October 2007, were treated with corticosteroid and analyzed retrospectively using SCORTEN, a severity‐of‐illness scoring system for TEN/SJS prognosis, to evaluate efficacy. For patients admitted after January 2001, additional therapy with a dose of 0.4 g/kg/day of IVIG for 5 days was applied. Results In the 45 patients with TEN treated without IVIG, 8.63 patients were expected to die based on the SCORTEN system, but 10 deaths were observed. Standardized mortality ratio (SMR) analysis [(Σobserved deaths/Σexpected deaths) × 100] suggested that patients with TEN treated with systemic corticosteroid were 16% more likely to die than those treated with routine therapy (SMR = 1.16; 95% confidence interval, 0.56–2.13). In the further study of combination therapy, 12 patients with TEN and eight patients with SJS were admitted. There were two deaths in the TEN group and one death in the SJS group, with 3.51 deaths expected on the basis of the SCORTEN system. SMR analysis showed that combination therapy had a tendency to reduce the mortality rate of TEN (SMR = 0.85; 95% confidence interval, 0.18–2.50). Nevertheless, in both the TEN and SJS groups, the difference in mortality rate between the two therapies was not statistically significant (P = 0.651 and P = 1, respectively). In patients with TEN, combination therapy also reduced significantly the time of arrested progression (P = 0.019) and the total hospitalization time (P = 0.043), but could not reduce the time to the tapering of corticosteroid (P = 0.96). In SJS patients, the times of arrested progression and hospitalization were also reduced significantly (P = 0.019 and P = 0.0475, respectively). Likewise, the time to the tapering of corticosteroid was not reduced (P = 0.122). Conclusion Combination therapy with corticosteroid and IVIG exhibited a tendency to reduce the mortality rate in comparison with the solo administration of corticosteroid. The decrease in the mortality rate, however, was not statistically significant. Combination therapy also arrested progression earlier and decreased the hospitalization time, meaning that the total dose of corticosteroid may be reduced. Combination therapy, however, did not lead to earlier tapering of corticosteroid. No severe adverse effects of IVIG were found during treatment.     

Open trial of ciclosporin treatment for Stevens–Johnson syndrome and toxic epidermal necrolysis

Background Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute mucocutaneous reactions associated with poor prognosis. The treatment is mainly symptomatic, based on supportive care. Until now, several curative treatments have been proposed without evidence of effectiveness. Objectives To evaluate the effect of ciclosporin on SJS and TEN after a short series had suggested a benefit. Methods We conducted an open, phase II trial to determine the safety and possible benefit of ciclosporin. Among the 45 consecutive patients admitted for SJS/TEN from March 2005 to September 2007, 29 fulfilled inclusion criteria. Ciclosporin was administered orally (3 mg kg^?1 daily for 10 days) and tapered over a month. Clinical and biological evaluations were performed sequentially. Predicted death rate was estimated with a validated prognostic score (SCORTEN). Results Twenty‐nine patients were included at a mean ± SD of 2·8 ± 1·8 days after onset. The final diagnosis was SJS (n = 10), SJS/TEN overlap (n = 12) and TEN (n = 7). One month of treatment was completed in 26. Ciclosporin was stopped after more than 10 days in three cases for side‐effects including posterior leucoencephalopathy (n = 1), neutropenia (n = 1) and nosocomial pneumopathy (n = 1). Ciclosporin dosage was tapered earlier than scheduled in two cases for alteration in renal function. The prognostic score predicted 2·75 deaths; none occurred (P = 0·1). Mean epidermal detachment remained stable in 18 of 29 cases (62%). The mean ± SD hospital stay was 16·2 ± 9·1 days. Conclusions Both the death rate and the progression of detachment seemed lower than expected, suggesting a possible usefulness of ciclosporin in SJS and TEN that needs to be confirmed.     

Distinguishing between erythema multiforme major and Stevens-Johnson syndrome/toxic epidermal necrolysis immunopathologically

The early clinical presentations of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are similar to that of erythema multiforme major (EMM). Cytotoxic molecules, especially granulysin, are expressed in the skin lesions of SJS/TEN and cause extensive keratinocyte death. It is postulated that the function of regulatory T cells (Treg) in SJS/TEN is inadequate. This study examined whether an immunohistological examination of cytotoxic molecules and the immunophenotype of Treg is useful for discriminating SJS from EMM in the early period. Over the past 9 years, the lesional skin of 14 patients with SJS/TEN and 16 patients with EMM was biopsied. Double immunofluorescence labeling of CD8 and granulysin, perforin, or granzyme B was performed, and immunohistochemical analyses of granulysin, perforin, granzyme B, CD1a, CD3, CD4, CD8, CD68 and Foxp3 were conducted using a highly sensitive indirect immunoperoxidase technique. The number of cells positive for each antibody per five high‐power fields was counted. The proportions of granulysin⁺ cells/CD8⁺ cells (P = 0.012) and perforin⁺ cells/CD8⁺ cells (P = 0.037) in SJS/TEN were significantly higher than in EMM. The number of Foxp3⁺ cells/five high‐power fields in SJS/TEN was significantly lower than in EMM (P = 0.004). Similarly, the number of CD4⁺ cells/five high‐power fields in SJS/TEN was significantly lower than in EMM (P = 0.0017). These data suggest that these panels of antibodies for labeling cytotoxic molecules, CD4 and Treg are useful for discriminating early SJS/TEN and EMM with a skin biopsy.