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.     

The CD40/CD40 ligand system is expressed in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum

Background Erythema multiforme (EM) and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are determined by a dysregulation of cellular immunity. Objectives To evaluate the effector role of cellular immunity and the involvement of the CD40/CD40 ligand (CD40L) system in the pathogenesis of EM and SJS/TEN. Methods Biopsy specimens from eight patients with EM and six with SJS/TEN were stained for immunohistochemical examination using the alkaline phosphatase/antialkaline phosphatase method. The monoclonal antibodies used included those to CD1a, CD4, CD8, CD40, CD40L, CD68, Fas, Fas ligand (FasL) and myeloperoxidase. Results The cellular infiltrate in both EM and SJS/TEN lesions was composed mainly of T lymphocytes and CD68+ macrophages. We also detected large amounts of neutrophils. Fas and FasL were very highly expressed in SJS and TEN, but weakly in EM. CD40 staining was strong in all tissue sections; there were numerous CD40L+ cells in SJS/TEN but much fewer in EM. Conclusions Activated T lymphocytes and macrophages, but also neutrophils, are presumably the main triggers of mucocutaneous damage in the SJS/TEN disease spectrum. The Fas/FasL system is significantly expressed in SJS/TEN lesions, but not in EM, where this apoptotic pathway presumably does not play a pivotal role in the epidermal damage. We suggest that the CD40/CD40L system may represent an important pathway of induction of SJS/TEN lesions, while in EM it would contribute to the immunoinflammation only as a second‐line mechanism.     

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.     

Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of treatment options

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous reactions that are medication-induced in most instances. While the clinical manifestations of SJS and TEN are well-defined, the optimal treatment for these disorders is not. Case reports have shown benefit with the use of a variety of agents including tumor necrosis factor-alpha inhibitors and cyclophosphamide, whereas thalidomide was associated with an increased mortality. Plasmapheresis and cyclosporine have also demonstrated efficacy anecdotally, albeit with an even smaller number of cases in the literature. Most of the reporting has focused on the use of systemic corticosteroids and intravenous immunoglobulin (IVIG) for these severe reactions. The majority of studies analyzing the use of IVIG in the treatment of SJS/TEN show a benefit, though more recent series cast doubt upon this conclusion. The results of these studies are summarized in this present review study.     

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).     

Update on pathobiology in Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are mainly induced by a variety of drugs. Once considered to be unpredictable, significant progress has been achieved in understanding the pathological mechanisms underlying such reactions. Recent studies suggested that SJS/TEN is a specific immune reaction where human leukocyte antigen (HLA) alleles specific for certain drugs in defined populations are involved in the activation of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Upon the activation, various cytotoxic and immunological signals, including but not limited to Fas/Fas ligand, perforin/granzyme B, and granulysin are launched to mediate the disseminated keratinocyte death in SJS/TEN. This review provides an update on the pathobiology of SJS/TEN in both the genomic and immunologic perspectives. The knowledge gained from these cutting-edge studies will form the basis for better prevention and management of SJS/TEN.     

Stevens-Johnson综合征/中毒性表皮坏死松解症角质形成细胞死亡机制的研究进展

角质形成细胞的凋亡涉及代谢及免疫机制,前者可能是亲电子的药物活性代谢产物经线粒体途径诱导凋亡.Stevens-Johnson综合征免疫机制则较复杂,CD8+细胞毒T细胞、自然杀伤细胞、单核细胞及调节T细胞等免疫细胞参与发病.肿瘤坏死因子α、可溶性FasL、颗粒溶素、肿瘤坏死因子相关凋亡诱导配体和肿瘤坏死因子样弱凋亡因子等细胞因子参与了凋亡作用的放大.在角质形成细胞的坏死中,警报素家族成员S100A、α防御素、高迁移率族蛋白B1均参与.     

Pediatric toxic epidermal necrolysis treated successfully with infliximab

Successful management of toxic epidermal necrolysis (TEN) with tumor necrosis factor‐α inhibitors has been described in adults. We present a case of a 7‐year‐old boy with infection‐associated TEN, diagnosed by typical clinical and histopathological features, most likely caused by Mycoplasma pneumoniae. Treatment with a single dose of infliximab 5 mg/kg intravenously on day 5 after the onset of symptoms was followed by cessation of all blister formation over 3 days and complete resolution within a week. Sequelae were mild, consisting of postinflammatory hyperpigmentation and dry eyes.     

Low N-acetylating capacity in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis*

Abstract Low constitutive N-acetylating capacity has been implicated as a predisposing factor for the development of adverse reactions to certain drugs. This prompted us to investigate whether the N-acetylating capacity of patients with serious cutaneous adverse reactions, i.e., Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) differed from that of healthy control subjects. N-acctylating activity was measured in hair root cells by preparing a homogenate from freshly extracted hair roots and assessing acetyl-CoA-dependent N-acetylation by RP-HPLC using 2-aminofluorene as a substrate. Samples were obtained from hospitalized patients suffering from acute SJS and TEN or from healthy controls. All patients with SJS and TEN were found to have a low N-acetylating capacity (0.85 nmol/mg/min compared to 2.21 nmol/mg/min in controls, p<0.05). Based on these findings, a low constitutive N-acetylating capacity may be one of the predisposing factors for the development of serious cutaneous adverse reactions to drugs that require N-acetylation in these patients.     

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.     

重症多形红斑与中毒性表皮坏死松解症患者的临床对比研究

目的探讨重症多形红斑(SJS)与中毒性表皮坏死松解症(TEN)的临床特点与临床治疗。方法对9例SJS和4例TEN住院患者的临床资料进行回顾性分析。结果 SJS组和TEN组患者中药物为最常见病因。TEN组的皮损范围、损害程度、粘膜病变均较SJS组更广泛、更严重。TEN患者主要表现为全身表皮松解,而SJS患者以靶形红斑为特征。TEN患者较SJS患者更易出现并发症。TEN患者病程急性期和恢复期时间均长于SJS患者。9例SJS和4例TEN患者早期均予以足量糖皮质激素治疗,TEN患者同时联用免疫球蛋白,13例患者均获痊愈。结论药物是SJS和TEN发病最主要的原因。TEN患者较SJS患者病变广泛且严重。药物诱发的SJS和TEN患者早期使用足量激素十分必要,TEN患者尚需静脉联用免疫球蛋白,提高抢救成功率。     

SCORTEN和ABCD-10评估Stevens-Johnson综合征/中毒性表皮坏死松解症预后的比较

【摘要】 目的 比较中毒性表皮坏死松解症（TEN）疾病严重程度评分（SCORTEN）及ABCD-10评分系统对Stevens-Johnson综合征（SJS）/TEN患者出现死亡结局的预测评估效能。方法 对2010年1月至2021年4月于四川省人民医院住院治疗的85例SJS/TEN患者的临床数据进行回顾性分析。比较SCORTEN及ABCD-10每个分数层患者的预期死亡率及实际死亡率,采用受试者操作特征（ROC）曲线及Hosmer-Lemeshow拟合优度检验评估SCORTEN及ABCD-10对死亡的预测力及校准度。结果 85例患者中男37例,女48例,年龄14 ~ 88（52.36 ± 19.31）岁,其中SJS 61例,SJS/TEN重叠6例,TEN 18例。死亡10例,病死率为11.76%。在SCORTEN和ABCD-10的危险因素中,年龄 > 40岁或 ≥ 50岁、入院第1天表皮剥脱 > 10%体表面积、心率 > 120次/min、血清尿素氮 > 10 mmol/L、血清碳酸氢盐 < 20 mmol/L与该组患者死亡存在统计学相关性（χ2值分别为4.46、6.18、25.50、15.13、7.59、8.38,均P < 0.05）,而伴恶性肿瘤、血清葡萄糖水平 > 14 mmol/L及入院前透析与死亡无统计学相关性（χ2值分别为0.35、0.10、1.38,均P > 0.05）。SCORTEN和ABCD-10每个分数层患者的预期死亡率与实际死亡率差异均无统计学意义（均P > 0.05）。ROC曲线显示SCORTEN及ABCD-10均对死亡有良好的预测力（曲线下面积分别为0.874、0.867,95% CI分别为0.758 ~ 0.990、0.773 ~ 0.962）,但SCORTEN的模型拟合度优于ABCD-10（P值分别为0.944、0.048）。结论 SCORTEN及ABCD-10评分系统均可在早期较准确地预测SJS/TEN患者的死亡概率,其中以SCORTEN校准更好,预测性能更优。     

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Are Severity Variants of the Same Disease which Differs from Erythema Multiforme

A new classification, based on the pattern and distribution of cutaneous lesions, separates erythema multiforme major from Stevens-Johnson syndrome. A retrospective reclassification of 76 cases supported the validity of that separation by demonstrating differing causes and pathology. Another prospective international case-control study found differing demographic characteristics and risk factors between erythema multiforme major on the one hand and Stevens-Johnson syndrome or toxic epidermal necrolysis on the other. Erythema multiforme major was mainly related to Herpes virus infection, while Stevens-Johnson syndrome and toxic epidermal necrolysis were associated with drug reactions.     

Stevens-Johnson综合征/中毒性表皮坏死松解症诊疗专家共识

Stevens-Johnson综合征（SJS）/中毒性表皮坏死松解症（TEN）是一种严重的皮肤-黏膜反应,绝大多数由药物引起,以水疱及泛发性表皮松解为特征,可伴发一系列系统症状,包括多器官功能衰竭综合征等,具有较高的死亡风险。中华医学会皮肤性病学分会药物不良反应研究中心组织相关专家,在国内外最新共识、指南及医学证据基础...     

Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis

Patch testing may help to assess the culpability of a drug in an adverse reaction. Our aim was to study patch testing in severe cutaneous ad verse drug reactions [ADRs] (Stevens-Johnson syndromeitoxic epidermal necrolysis (SJS/TEN). acute genera exanthematous pustulosis (AGEP), and other cutaneous ADRs). 59 patients with cutaneous ADRs were included: 22 had SJS/TEN. 14 AGEP, and 23 other cutaneous ADRs. Patients were patch tested with the suspect drug and with H standard series of drugs. 2 patients among the 22 SJSTEN cases had a relevant positive test. 7 patients among the 14 AGEP cases had a relevant positive test. 6 patients among the 23 other cutaneous ADRs had a relevant positive test. Our results suggest that patch testing has a weak sensitivity in SJS'TEN and is not appropriate in these diseases. Patch testing seems more adapted to other cutaneous ADRs, such as AC it: P. in which the proportion of positive patch tests was significantly higher (P<0.02). Nevertheless, the difference of sensitivity of patch testing in SJS TEN, AGEP or other cutaneous ADRs could be linked not only to the clinical type of eruption, but also lo the different spectrum of culprit drugs in each type of eruption.