Intravenous Immunoglobulin Use in Patients with Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome

Intravenous immunoglobulin (IVIg) has been proposed as a treatment for toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS). A comprehensive search of the literature was conducted to examine the efficacy and safety of IVIg in TEN and SJS patients. Seventeen relevant articles (14 TEN, 3 SJS) were identified. Only three of the TEN studies and one of the SJS studies were prospective; retrospective studies were the most common study design published. Information regarding disease severity, IVIg use, response, and hospitalization were recorded and cumulated. Aggregate level statistics were calculated. The average IVIg doses used were 0.8 +/- 0.4 g/kg/day for a mean duration of 4.0 +/- 1.0 days in TEN patients and 0.8 +/- 0.2 g/kg/day for 3.4 +/- 1.0 days in SJS patients. The clinical experience of IVIg use in TEN and SJS patients was positive in most cases. However, more studies need to be conducted to confirm the benefit of IVIg use in patients with TEN or SJS.     

Profile and pattern of Stevens-Johnson syndrome and toxic epidermal necrolysis in a general hospital in Singapore: treatment outcomes

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially life-threatening, reactions to medications. Both conditions have significant morbidity and mortality. The aim of this study was to document the epidemiological features, aetiologies, treatment and clinical outcomes of retrospectively reviewed data of all patients with SJS or TEN treated from January 2004 to November 2010 in a general hospital. There were 18 cases of SJS, seven cases of SJS/TEN overlap and three cases of TEN. Mean age was 50.6 years, with a range of 13-85 years. The male/female ratio was 1. Drugs accounted for 26 cases; one case was caused by Neisseria gonorrhoea infection. Anti-convulsants (35.7%) were the most common implicated drugs followed by antibiotics (28.5%), non-steroidal anti-inflammatory drugs (NSAIDS) (14.3%), allopurinol (7.1%) and traditional Chinese medication (7.1%). In seven cases, multiple drugs were implicated. Most SJS cases (88%) were treated with corticosteroids, of which 61% were given high-dose systemic corticosteroids. No infective complications were observed. Six out of the seven SJS/TEN overlap syndrome and all three TEN cases were given intravenous immunoglobulins. One patient with TEN died. In conclusion, anti-convulsants, especially carbamazepine, were the most frequently implicated drugs, followed by antibiotics and NSAIDS. High-dose corticosteroids were effective in SJS, whereas intra-venous immunoglobulin were useful in TEN and SJS/TEN overlap syndrome.     

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.     

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.     

Toxic epidermal necrolysis and Stevens-Johnson syndrome. An epidemiologic study from West Germany

Little work has been carried out on the epidemiology of the two serious skin reactions--toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS). We collected details of all the hospitalized cases of TEN and SJS in the Federal Republic of Germany for the years 1981 through 1985 inclusive. Inquiries by telephone, letter, and personal visits produced an overall response of 91%; 259 cases of TEN and 315 cases of SJS were identified. From these data, we were able to calculate an overall annual risk of 0.93 and 1.1 per million for TEN and SJS, respectively. The average age group was higher for TEN (63 years) than for SJS (25 years). Women are markedly more at risk for TEN in the ratio of 2:1, these figures being reversed for SJS. The mortality was 34% (87/259) for TEN and only 1% (2/315) for SJS. An association with previous medication defined as "definite, probable, possible" could be established for 89% of cases of TEN and 54% of cases of SJS. The drugs most commonly involved were antibiotics (TEN, 40%; SJS, 34%), followed by the analgesics (TEN, 23%; SJS, 33%). As with the drug groups, the incidences being based on the defined daily doses, were high for sulfonamides, beta-lactam antibiotics, and some nonsteroidal anti-inflammatory drugs.     

Stevens–Johnson syndrome in two patients treated with cranial irradiation and phenytoin

Stevens-Johnson syndrome (SJS) is a severe cutaneous eruption that most often appears as an adverse reaction to medication. In this report, we present two patients diagnosed with SJS, which developed in patients with brain tumour, after receiving cranial irradiation and phenytoin. Concomitant application of these two therapies may play an important role in the occurrence of the disease.     

Stevens-Johnson syndrome limited to multiple sites of radiation therapy in a patient receiving phenobarbital

Stevens-Johnson syndrome (SJS) is a severe cutaneous eruption that most often appears as an adverse reaction to a medication. There have been 21 reported cases of atypical erythema multiforme, toxic epidermal necrolysis, and SJS arising in patients receiving radiation therapy in addition to phenytoin, phenobarbital, or carbamazepine. We report the second case of SJS resulting from concomitant phenobarbital and radiation therapy, in which the eruption was limited to the sites of radiation, which were multiple.     

Clinical profiles of Stevens–Johnson syndrome among Thai patients

The objective of this study was to demonstrate the clinical profiles of Stevens–Johnson syndrome (SJS) in Thai patients, and to compare those clinical features between younger and older patients. Medical records of all patients with SJS who were admitted to Srinagarind Hospital Medical School, Khon Kaen, Thailand, from January 2002 to December 2014 were reviewed. Epidemiological features, etiologies, treatment and clinical outcomes were collected. There were 45 patients with SJS during the 10‐year period. Females were the majority (57.8%) and the median age was 49 years. Hepatitis was the most frequent complication (67.5%). Phenytoin (15.6%), sulfonamide drugs (15.6%) and allopurinol (13.3%) were implicated as leading causes of SJS. Steroids were prescribed in 37 cases (82.2%). The mortality rate was 4.4%. Comparing older patients to younger patients, allopurinol appeared to be the main instigating drug to develop SJS with an odds ratio of 5.6 (95% confidence interval, 2.8–10.6). In conclusion, clinical features of Thai patients with SJS were similar to other reports. Allopurinol had the strongest association with SJS in older patients as compared to the younger ones.     

Association of HLA-B*1502 allele with carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome in the multi-ethnic Malaysian population

Background Carbamazepine (CBZ), a frequently used anticonvulsant drug, is one of the most common causes of life‐threatening cutaneous adverse drug reactions such as toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS). Recent studies have revealed a strong association between HLA‐B*1502 and CBZ‐induced TEN/SJS in the Taiwan Han Chinese population. Objectives This study is aimed to investigate the association between human leucocyte antigens (HLA) and CBZ‐induced TEN/SJS in the multi‐ethnic Malaysian population. Methods A sample of 21 unrelated patients with CBZ‐induced TEN/SJS and 300 race‐matched, healthy controls were genotyped for HLA‐A, ‐B and ‐DR using polymerase chain reaction (PCR). Allele frequencies were compared. Results HLA‐B*1502 was present in 75.0% (12/16) of Malay patients with CBZ‐induced TEN/SJS but in only 15.7% (47/300) of normal controls (odds ratio 16.15, 95% confidence interval 4.57–62.4; corrected P‐value = 7.87 × 10^?6), which suggests a strong association between HLA and CBZ‐induced TEN/SJS. Additionally, HLA‐B*1502 was found in all three Chinese and two Indian patients. Existing data show that frequencies of the HLA‐B*1502 allele are generally much higher in Asian populations than in White European populations, which explains the higher incidences of SJS and TEN in Asian countries. Conclusions HLA‐B*1502 is strongly associated with CBZ‐induced TEN/SJS in the Malay population in Malaysia, as has been seen in Han Chinese in Taiwan. This indicates that the genetic association apparent in the incidence of CBZ‐induced TEN/SJS is linked with the presence of HLA‐B*1502, irrespective of racial origin. Screening of patients for this genetic marker can help to prevent the occurrence of TEN/SJS.     

药物所致重症多形红斑和中毒性表皮坏死松解症的临床研究

对药物所致征症多形红斑（ＳＪＳ）和中毒性表皮松解症（ＴＥＮ）进行了对比研究。两者最常见的致敏解药物是解镇痛药，其次是抗生素类和镇静抗癫痫药。ＳＪＳ和ＴＥＮ的发病年龄、性别和潜伏期无差异，但ＴＥＮＲ 发热时间、急性期和恢复期时间明显长于ＳＪＳ，发热程度、粘膜损害程度和合并症发生率明显高于ＳＪＳ。ＳＪＳ预后良好，无１例死亡，ＴＥＮ的死亡率高达３９％。关于皮质类固醇激素在治疗ＴＥＮ中的应用，我们认为早期     

Mycoplasma pneumoniae–Induced Recurrent Stevens–Johnson Syndrome in Children: A Case Report

Mycoplasma pneumoniae, the major pathogen of primary atypical pneumonia, is reported as the most common infectious agent associated with Stevens–Johnson syndrome (SJS) in children. For that reason it is important to consider mycoplasma infection also in the absence of classical pulmonary symptoms. SJS is a rare and acute, self‐limited disease, characterized by severe inflammation and necrosis of two or more mucous membranes. We report the case of a 12‐year‐old boy with a diagnosis of SJS induced by M. pneumoniae infection. The patient's SJS relapsed 8 months after discharge. When the condition is recurrent, it is important early on to identify the cause of a single episode to optimize care and therapeutic choices.     

Stevens‐Johnson syndrome and toxic epidermal necrolysis in children: a review of the experience with paediatric patients in a University Hospital

Background Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life‐threatening drug reactions considered to be part of the spectrum of a single pathological process. Objective To describe the clinical and epidemiological characteristics of SJS/TEN in children attended at our hospital. Materials and methods Retrospective study of children diagnosed with SJS/TEN between 1999 and 2009 in a University Hospital provided with regional‐level burn and paediatric intensive care units. Results We found 14 paediatric patients (eight SJS and six TEN). They presented an average of 60% of the body surface area affected and 31% of epidermal sloughing. The average of suspected drugs was 1.7 per patient, anticonvulsants (carbamazepine, phenytoin and lamotrigine) and antibiotics (penicillin and macrolides) being the most frequent ones. Silver sulfadiazine was the topical treatment most frequently used, 86% of patients received systemic steroids and 28.5% intravenous immunoglobulins. One patient died. Conclusions The SJS/TEN complex is a true dermatological critical condition that also affects children. Any drug can be the causative agent, more frequently anticonvulsants and antibiotics. Depending on the extension of the affected body surface, patients should be rapidly admitted to a critical care area with experience in the care of burn patients. Discontinuation of the suspected offending drugs is mandatory. Optimal supportive care and management of denuded skin areas are still the mainstay of treatment. The use of specific therapies remains controversial. Compared with adults, the disease in children seems to be milder with lower mortality.     

Clinical Pattern of Cutaneous Drug Eruption among Children and Adolescents in

Abstract: Various types of cutaneous drug eruptions and the Incriminating drugs were analyzed tn 50 children and adolescents up to 18 years of age (34 or 65% boys, 16 or 32% girls). Thirteen (26%) patients had a maculopapular rash, 11 (22%) a fixed drug eruption (FDE), 10 erythema multiforme (EM), 6 (12%) toxic epidermal necrolysis (TEN), 5 (10%) Stevens-Johnson syndrome (SJS), 3 (6%) urticaria, and 2 (4%) erythroderma. The Incubation period for maculopapular rashes, SJS and TEN due to commonly used antibiotics and sulfonamides was short, a few hours to two to three days, reflecting reexposure, and for drugs used sparingly such as antiepileptics and antitubereulosis agents, was approximately one week or more, suggesting a first exposure. Antibiotics were responsible for cutaneous eruptions in 27 patients, followed by antlepileptics In 17, analgin in 4, and metronidazole and albendazole in 1 each. Cotrimoxazole, a combination of sulfamethoxazole and trimethoprim, was the most common antibacterial responsible for eruptions (11 patients), followed by penicillin and its semisynthetlc derivatives (8 patients), sulfonamide alone (3 patients), and other antibiotics (4 patients). Antiepileptics were the most frequently incriminated drugs in EM, TEN, and SJS. The role of systemic corticosteroids in the management of SJS and TEN is controversial. We administered prednisolone or an equivalent corticosteroid 2 mg/kg/day for 7 to 14 days. With this dosage the mortality rate in the combined patients with TEN and SJS was 18.2%. Our limited experience suggests that these drugs might still have a role in the management of SJS and TEN In children and adolescents.     

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。     

重症多形红斑型药疹52例和中毒性表皮坏死松解症31例回顾性分析

目的比较重症多形红斑(SJS)和中毒性表皮坏死松解症(TEN)的临床特征和实验室检查指标的差异。方法对2000年7月-2012年2月本院收治的83例SJS和TEN患者的临床资料进行回顾性分析,用SCORTEN评分系统对疾病的严重程度和病人的预后进行评估。结果引起SJS和TEN的药物以抗生素为主,其次是非甾体类抗炎药。TEN组的电解质异常的例数明显高于SJS组(P<0.05);肝功能损害是SJS和TEN最常见的并发症;SJS组和TEN组共有81例给予系统用糖皮质激素治疗,2例仅用人免疫球蛋白治疗,SJS组7例和TEN组15例给予激素联合人免疫球蛋白治疗。SCORTEN评分超过3分的有4例,其中1例死亡。结论抗生素是引起重症药疹最常见的药物,系统应用糖皮质激素尤其是联合人免疫球蛋白治疗可能是降低SJS和TEN死亡率的有效手段之一。     

Drug rash with eosinophilia and systemic symptoms vs toxic epidermal necrolysis: the dilemma of classification

According to contemporary vernacular, when the cutaneous manifestations of drug rash with eosinophilia and systemic signs (DRESS) syndrome are those of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), the condition is defined as "DRESS syndrome with severe cutaneous reactions". In this article, we have presented arguments for and against including patients with skin lesions of the SJS/TEN syndromes who also have fever (practically all of the patients) and internal organ involvement (most of the patients) under the definition of DRESS syndrome. After weighing the arguments for and against this alteration of definition, we conclude that it makes more sense for patients with SJS/TEN to be classified as such and not be lumped together under the misleading label of DRESS syndrome.     

Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with lupus erythematosus: a descriptive study of 17 cases from a national registry and review of the literature

Background Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions with high morbidity and mortality. Some expressions of lupus erythematosus (LE) may cause enormous difficulties in differentiating them from SJS and TEN by showing large areas of sheet‐like epidermal necrosis. Objective To evaluate clinically and histopathologically probable or definite cases of SJS/TEN with a history of systemic or other LE [(S)LE]. Methods This was a retrospective analysis of validated cases of SJS/TEN with a history of (S)LE, based on a large population‐based national registry. Results Among 1366 patients with SJS/TEN, 17 with a sufficiently documented history of (S)LE and representative histological material could be identified, suggesting a considerable over‐representation of LE in patients with SJS/TEN. Eight of these showed clinically and/or histopathologically some LE‐characteristic features interfering with the diagnosis of SJS/TEN. Differentiation could be elaborated on clinical and histopathological grounds: four patients were classified as SJS/TEN with a preceding (S)LE exacerbation and/or LE‐typical histopathological features, and four as ‘TEN‐like’ (S)LE. Conclusion Most patients with SJS/TEN and a history of (S)LE demonstrate clinical and histopathological properties allowing clear differentiation. However, occasionally acute cutaneous manifestations of (S)LE and SJS/TEN can be phenotypically similar, caused by extensive epidermal necrosis. Although no feature by itself is conclusive, a combination of recent (S)LE exacerbation, evident photodistribution, annular lesions and absent or only mild focal erosive mucosal involvement may favour LE over SJS/TEN clinically. Histopathologically, in particular, junctional vacuolar alteration, and the presence of solitary necrotic keratinocytes at lower epidermal levels, combined with moderate to dense periadnexal and perivascular lymphocytic infiltrates with a variable presence of melanophages, and mucin point to a LE‐related origin.     

Serum and blister-fluid elevation and decreased epidermal content of high-mobility group box 1 protein in drug-induced Stevens–Johnson syndrome/toxic epidermal necrolysis

Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, severe, skin blistering conditions in which areas of skin die and detach. They actually represent a single disease with a spectrum of severity: less than 10% body surface area detachment in SJS and more than 30% in TEN. It affects around 500 people in the UK each year and is most commonly caused by a reaction to a wide-range of commonly prescribed drugs. This study brought together researchers and patients from the U.K., Spain, Taiwan and the U.S.A. and aimed to determine levels of a protein called high mobility group box 1 (HMGB1) in the serum (part of the blood), blister fluid and skin biopsy tissue of SJS/TEN patients. HMGB1 is a protein which is known to be a marker (biological sign) of a) tissue/cell injury and b) activation of the immune response, both of which occur in SJS/TEN. The authors detected elevated serum HMGB1 levels in SJS/TEN patients at the time of reaction in three independent patient populations, and also extremely high levels in patients’ blister fluid. Levels of HMGB1 in the epidermal (upper) layer of the skin were considerably decreased in SJS/TEN patients but not healthy control or drug-induced rash skin. The decrease in HMGB1 levels in the epidermis of the skin appears to occur prior to blistering and may represent an early indicator. In addition, levels of HMGB1 appear to be retained at the junction between the epidermis and the next layer of skin, called the dermis, which may suggest a potential role for HMGB1 in the mechanism by which the layers become detached in SJS/TEN patients. The authors conclude that serum HMGB1 may not represent a good clinical marker of SJS/TEN, but that decreased levels of it in the skin may be a sign of the early onset of skin blistering, and could have a key role in the mechanism by which this occurs.     

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.     

Drug-Induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare (occurring in approximately 2 to 3 people/million population/year in Europe and the US), life-threatening, intolerance reaction of the skin. It is most often caused by drugs (most commonly sulfonamides, nonsteroidal anti-inflammatory drugs, antimalarials, anticonvulsants, and allopurinol). SJS/TEN is characterized by a macular exanthema (‘atypical targets’) which focusses on the face, neck, and the central trunk regions. Lesions show rapid confluence, a positive Nikolsky’s sign, and quickly result in widespread detachment of the epidermis and erosions. Mucosal, conjunctival, and anogenital mucous membranes are prominently involved. Histopathology shows satellite cell necrosis in the early stages progressing to full thickness necrosis of the epidermis, contrasting with rather inconspicuous inflammatory infiltrates of the dermis. Damage to the skin is thought to be mediated by cytotoxic T lymphocytes and mononuclear cells which induce apoptosis in keratinocytes expressing drug-derived antigens at their surfaces. No guidelines for the treatment of SJS/TEN exist since no controlled clinical trials have ever been performed. The controversy over whether systemic corticosteroids should be used to curtail progression is still unresolved; while many authors agree that corticosteroids do in fact suppress progression, it is obvious that they also greatly enhance the risk of infection, the complication which most frequently leads to a fatal outcome. It appears reasonable to only administer corticosteroids in the phase of progression and to withdraw them as soon as possible, and to add antibacterials for prophylaxis. Recently, in a small series of patients, intravenous immunoglobulins were presumed to be effective by the blockade of lytic Fas ligand-mediated apoptosis in SJS/TEN. However, these results have to be confirmed by large clinical trials. Supportive treatment and monitoring of vital functions is of utmost importance in SJS/TEN, and out-patient treatment is unacceptable. Recovery is usually slow, depending on the extent and severity and the presence of complications, and may take 3 to 6 weeks. Skin lesions heal without scars as a rule, but scarring of mucosal sites is a frequent late complication, potentially leading to blindness, obliteration of the fornices and anogenital strictures. There is no reliable laboratory test to determine the offending drug; diagnosis rests on the patient’s history and the empirical risk of drugs to elicit skin SJS/TEN. Provocation tests are not indicated since re-exposure is likely to elicit a new episode of SJS/TEN of increased severity.