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.     

Erythema multiforme majus (Fuchs syndrome) associated with Mycoplasma pneumoniae infection in two patients

In Germany Fuchs syndrome is used to describe a variant of erythema multiforme majus which mainly involves the mucosal surfaces. As the skin may be completely unaffected, it is an under‐recognized diagnosis and often difficult to confirm. Clinical features involve erythema, erosions and ulcerations of the oral mucosa. In most cases there is severe conjunctivitis and sometimes the genital mucosa is involved. Most cases of Fuchs syndrome are triggered by infections; herpes simplex virus and Mycoplasma pneumoniae are the most common causes. We describe two women presenting with Fuchs syndrome after respiratory illness caused by Mycoplasma pneumoniae.     

Case of fertility treatment‐induced Stevens‐Johnson syndrome with a severe ocular complication

Pharmacological regimens with multiple medications are being used in fertility treatments. Herein, we report a case of a 40‐year‐old Japanese woman who developed Stevens‐Johnson syndrome (SJS) with a severe ocular complication during fertility treatment. Despite early multimodal interventions, including methylprednisolone pulse therapy and plasma exchange, her ocular complications persisted for more than a year. The four drugs administered in this case (cabergoline, medroxyprogesterone acetate, clomiphene, and intravenous human chorionic gonadotropin) have never been reported to induce SJS. Based on this case, we suggest that obstetricians, gynecologists, and dermatologists should be aware of fertility treatment‐induced severe drug eruptions.     

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).     

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.     

Ethosuximide‐induced Stevens–Johnson syndrome: Beneficial effect of early intervention with high‐dose corticosteroid therapy

We report two rare cases of childhood epilepsy patients who developed ethosuximide‐induced Stevens–Johnson syndrome (SJS). Unlike typical SJS, the initial eruption of both patients presented well‐demarcated, infiltrating firm papules mainly on the cheeks and the extensor aspects of the arms (case 1), and multiple vesicles on the soles and oral aphthosis (case 2), which closely mimicked viral exanthema. We diagnosed both patients with ethosuximide‐induced SJS, based on the dosing period and the positive results of drug‐induced lymphocyte stimulation test. Systemic corticosteroids are usually selected as a standard therapy for SJS, despite controversial results regarding their effectiveness. In case 1, an i.v. pulse therapy of methylprednisolone (30 mg/kg, 3 days consecutively) was initiated on day 7 from the onset of illness, and an i.v. immunoglobulin (400 mg/kg, 5 days consecutively) was added the following day. In case 2, an i.v. prednisone treatment (1 mg/kg, for 1 week) was initiated on day 4 from the onset. Eventually, the early therapeutic interventions resulted in good outcomes in both patients.     

肺炎支原体诱导的皮疹和黏膜炎8例临床特征及预后分析

【摘要】 目的 分析肺炎支原体诱导的皮疹和黏膜炎（MIRM）的临床特征及预后。方法 调阅中山大学附属第一医院2004年11月至2021年5月出院诊断为多形红斑/重症多形红斑或Stevens-Johnson综合征患者的资料,以MIRM诊断标准筛选出其中的MIRM患者,且排除了其他病因,分析其临床表现、实验室和辅助检查、治疗和预后。结果 8例符合MIRM诊断,其中男4例,女4例,发病年龄4 ~ 30（15.63 ± 9.16）岁。8例均有发热,其中5例有咳嗽、咽痛等上呼吸道前驱症状。所有患者均有口腔黏膜损害,其中5例有口唇血痂;7例有眼损害,表现为结膜充血及分泌物增多。所有患者均有皮损,表现为靶形损害5例、水疱4例。所有患者血清学肺炎支原体IgM均阳性。1例反复出现干咳等上呼吸道感染,每次发作与肺炎支原体感染密切相关,取外周血行全外显子测序显示,NLRC4和IRGM杂合突变。3例患者行皮损组织病理检查,符合多形红斑。7例系统使用糖皮质激素治疗,6例静脉注射免疫球蛋白,5例阿奇霉素,5例使用阿昔洛韦或伐昔洛韦或利巴韦林。平均随访2.9年,3例痊愈,1例失明,1例反复出现干咳和口腔溃疡及四肢皮疹,余3例分别出现眼睑板腺功能障碍、泪点狭窄及角膜上皮损害等眼部损害。结论 MIRM好发于儿童及年轻成人,多有发热、咽痛、咳嗽等前驱症状,黏膜损害明显,部分有皮肤靶形损害。多数患者单次发病后痊愈,个别反复发作者可能与自身炎症相关基因和感染相关基因突变有关。     

Influenza B virus infection and Stevens–Johnson syndrome

A 2‐year‐old boy with influenza B infection and rapidly worsening targetoid skin lesions with mucosal involvement was diagnosed with Stevens–Johnson syndrome (SJS) and treated with oseltamivir and intravenous immunoglobulin, with resolution of illness. Subsequent quadrivalent inactivated influenza vaccine was well tolerated. This case highlights the rarity of SJS in the setting of influenza B infection and addresses the safety of administering subsequent influenza vaccines to such individuals.     

Mycoplasma pneumoniae and mucositis - part of the Stevens-Johnson syndrome spectrum

Background: Mycoplasma pneumoniae may induce mucosal inflammation, referred to as M. pneumoniae-associated mucositis (MPAM). There is no generally accepted definition of MPAM, since there may be mucosal lesions only, or mucosal and minimal skin lesions. Patients and Methods: We conducted a literature review of MPAM, paying particular attention to pathogenesis, clinical manifestations, treatment decisions, and prognosis. Results: We identified 32 cases of MPAM (median age 13.5 years), whereof 23 patients were otherwise healthy children and young adolescents (72%). M. pneumoniae infection was associated with fever and respiratory symptoms in all calls; it was confirmed by serology (n = 30) and/or PCR (n = 9). Oral lesions were present in all cases, followed by ocular (97%) and uro-genital lesions (78%). Despite the syndrome's name postulating the absence of cutaneous involvement, minimal skin lesions occurred in 31%. Treatment regimens included systemic antibiotics (100%) and systemic anti-inflammatory treatment with corticosteroids (31%) or immunoglobulins (9%). Macrolides were given in 81%, with failure, relapse, and/or worsening in one-third of patients. No patient suffered long-term sequelae. Conclusion: MPAM is a distinct extra-pulmonary manifestation falling into the continuum of Stevens-Johnson syndrome. This entity may be due to inflammatory mechanisms suggesting that systemic anti-inflammatory treatment is even more important than antimicrobials.     

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.     

Efficacy of additional i.v. immunoglobulin to steroid therapy in Stevens–Johnson syndrome and toxic epidermal necrolysis

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and life‐threatening cutaneous adverse drug reactions. While there is no established therapy for SJS/TEN, systemic corticosteroids, plasma exchange and i.v. immunoglobulin (IVIG) have been used as treatment. The efficacy of IVIG is still controversial because total doses of IVIG used vary greatly from one study to another. The aim of this study was to evaluate the efficacy of IVIG, administrated for 5 days consecutively, in an open‐label, multicenter, single‐arm study in patients with SJS or TEN. IVIG (400 mg/kg per day) administrated for 5 days consecutively was performed as an additional therapy to systemic steroids in adult patients with SJS or TEN. Efficacy on day 7 of IVIG was evaluated. Parameters to assess clinical outcome were enanthema including ophthalmic and oral lesions, cutaneous lesions and general condition. These parameters were scored and recorded before and after IVIG. We enrolled five patients with SJS and three patients with TEN who did not respond sufficiently to systemic steroids before IVIG administration. All of the patients survived and the efficacy on day 7 of the IVIG was 87.5% (7/8 patients). Prompt amelioration was observed in skin lesions and enanthema in the patients in whom IVIG therapy was effective. Serious side‐effects from the use of IVIG were not observed. IVIG (400 mg/kg per day) administrated for 5 days consecutively seems to be effective in patients with SJS or TEN. IVIG administrated together with steroids should be considered as a treatment modality for patients with refractory SJS/TEN. Further studies are needed to define the therapeutic efficacy of IVIG.     

Rapid remission of Stevens–Johnson syndrome by combination therapy using etanercept and intravenous immunoglobulin and a review of the literature

Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are spectrum of rare, acute, and life‐threatening delayed‐type drug hypersensitivity reactions that are associated with high mortality rates. However, no therapeutic standard has been proposed for SJS/TEN. Here, we report a case of a patient diagnosed with Stevens–Johnson syndrome whose disease progression was halted by a single dose of etanercept and was treated successfully. In addition, we reviewed the literature reporting patients with SJS/TEN treated with similar regimens.     

Procalcitonin as a diagnostic indicator for systemic bacterial infections in patients with Stevens–Johnson syndrome/toxic epidermal necrolysis

Elevated serum procalcitonin (PCT) level has been reported to be a diagnostic index in systemic bacterial infections, but it can also increase in some non‐infectious inflammatory diseases. Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is a rare immune‐mediated cutaneous mucosal reaction which is susceptible to bacterial infections and may have elevated PCT levels. The value of serum PCT has not been assessed in series of SJS/TEN patients. We aimed to investigate the PCT levels in SJS/TEN patients with systemic bacterial infections (systemic infected group), with skin surface bacterial infections (skin surface infected group) and without infections (non‐infected group), to assess whether PCT was a valuable indicator for systemic bacterial infections in SJS/TEN patients. The PCT and C‐reactive protein (CRP) levels of 42 inpatients with SJS/TEN were retrospectively analysis. The receiver–operator curve (ROC) was used to determine the diagnostic efficacy of PCT for systemic bacterial infections in SJS/TEN patients. The results demonstrated that PCT levels in the systemic infected group were significantly higher than those in the other two groups (P < 0.05). There was no significant difference in CRP between the three groups. The cut‐off PCT level of 0.65 ng/mL calculated by ROC had optimal diagnostic efficacy, with sensitivity and specificity of 84.6% and 89.7%, respectively. PCT and severity‐of‐illness score for toxic epidermal necrolysis were positively correlated (P < 0.05). In conclusion, PCT is a valuable index and superior to CRP in detecting systemic bacterial infections in SJS/TEN patients. The level of PCT can partially reflect the severity of the disease.     

Incidence of Stevens–Johnson syndrome following combination drug use of allopurinol,carbamazepine and phenytoin in Taiwan: A case–control study

The goal of our study was to investigate the incidence of Stevens–Johnson syndrome (SJS), the frequency of SJS diagnosis, and the association between SJS and prior use of allopurinol, carbamazepine or phenytoin. This case–control study utilized data from the National Health Insurance Research Database (NHIRD) of Taiwan. Controls visited the emergency department of the same hospital for trauma or fractures (excluding burns) and used allopurinol, carbamazepine or phenytoin during the past 3 months. We determined whether patients were prescribed a combination of drugs in addition to allopurinol, carbamazepine or phenytoin within the last 3 months. We identified 1 853 985 controls and 7327 SJS‐diagnosed patients using the Taiwan NHIRD records for 2000–2008. Higher use of allopurinol (49.8%), carbamazepine (39.1%) or phenytoin (21.3%) was observed among patients (n = 3131) than among controls (n = 2858). The overall SJS incidence rate was 3.6/1 000 000. Drug combinations were uncommon (<10%) in patients or controls taking allopurinol. However, combination drug use exceeded 10% in patients taking carbamazepine or phenytoin. Logistic regression analysis of recent combination drug use revealed that phenobarbital, valproate, non‐steroidal anti‐inflammatory drugs (NSAIDs) including piroxicam and tenoxicam, and antibiotics including amoxicillin and cephalexin were strongly associated with SJS. Patients with gout or epilepsy taking allopurinol, carbamazepine or phenytoin should be evaluated carefully by physicians. Concurrent use of piroxicam, tenoxicam, phenobarbital, valproate, amoxicillin or cephalexin, in addition to carbamazepine or phenytoin, may increase the incidence of SJS.     

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.     

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.     

Role of nanocrystalline silver dressings in the management of toxic epidermal necrolysis (TEN) and TEN/Stevens–Johnson syndrome overlap

Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are severe mucocutaneous eruptions. There is currently no defined optimal approach to wound care. The objective of this study was to evaluate silver dressings in the wound‐care management of TEN and SJS/TEN syndrome overlap with a retrospective case review of nine patients with TEN and SJS/TEN overlap presenting to our institution. Nanocrystalline silver dressings appear to be useful in the rapid commencement of healing in these patients. TEN and SJS/TEN overlap are rare conditions. This contributed to a relatively small number of cases included in the study. The ease of application, antimicrobial properties and low frequency of change make nanocrystalline silver dressings ideal in TEN/SJS.     

Toxic epidermal necrolysis and Stevens‐Johnson syndrome at the Prague Burn Centre 1998–2008

Background Toxic epidermal necrolysis (TEN) and Stevens‐Johnson syndrome (SJS) are skin disorders characterized by extensive necrosis of the mucous membranes and the epidermis caused by an autoimmune response. Objectives  To present experience of treating TEN and SJS at the Prague Burn Centre (PBC) 1998–2008. Methods  22 patients with the diagnosis TEN or SJS were enrolled. We collected data including the extent of the skin involvement, the ratio of men : women, the average age, the mortality rate, presence of comorbidities, the length of hospital stay, the period from the first symptoms to the admission to the PBC, corticosteroids administration prior to admission. Results  82% patients had injuries larger than 30% of body surface area. The ratio of men : women was 1 : 1.5; the average age was 48.4 years; the mortality was 32%. Significant comorbidities were present in 41% of the cases. The average length of hospital stay was 12.9 days. The period from the first symptoms to the admission to the PBC was 9.6 days; corticosteroids were administered to 68% of the cases. Conclusion  Treatment strategies at the PBC are based upon a multidisciplinary approach and focus on the general principles of treating patients with extensive skin loss. Corticosteroids must be avoided, antibiotics are not indicated and intravenous immunoglobulins are not justified in the standard therapy. Early diagnosis, prompt transport to a burn center are essential for patients outcomes. The medical community should be informed about these rare but potentially life threatening diseases.