Long‐term complications of Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN): the spectrum of chronic problems in patients who survive an episode of SJS/TEN necessitates multidisciplinary follow‐up

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse reactions to drugs that cause a life‐threatening eruption of mucocutaneous blistering and epithelial sloughing. While the acute complications of SJS/TEN are well described, it is increasingly recognized that survivors may develop delayed sequelae, some of which can be associated with significant morbidity. Studies of long‐term SJS/TEN outcomes mostly focus on mucocutaneous and ocular complications. However, other internal organs, such as the respiratory tract and gastrointestinal tract, can be affected. Psychological sequelae are also frequent following the trauma of widespread epidermal necrolysis. An appreciation of the ‘chronic’ phase of SJS/TEN is needed by clinicians caring for individuals who have survived the acute illness. This review aims to provide an update on the breadth and range of sequelae that can affect patients in the months and years following an acute episode of SJS/TEN.     

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).     

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.     

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.     

Epidermal necrolysis: 60 years of errors and advances

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare conditions characterized by extensive epidermal detachment and mucositis. Both are associated with a high mortality rate and significant long‐term morbidity. Since the initial report introducing the term TEN in 1956, diagnosis of the condition has been fraught with difficulties that continue to exist today. The terms ‘erythema multiforme major’ (EMM) and SJS, and their relationship to TEN have also been confusing to clinicians. It is now recognized that EMM is a different entity from SJS and TEN in terms of demographics, causality and severity. SJS and TEN represent a continuum of disease, and differ only by the extent of epidermal detachment and therefore severity. The term ‘epidermal necrolysis’ (EN) is used in this article to describe the spectrum of disease that includes SJS and TEN. Important advances in understanding the pathomechanism and treatment of EN have been made over the years. These include the recognition of human leucocyte antigen (HLA) associations (e.g. HLA‐B*1502 with carbamazepine‐induced TEN) and understanding of the pathogenic roles of drug‐specific cytotoxic T cells and granulysin. It was previously believed that widespread keratinocyte death in EN is predominantly mediated by soluble Fas‐ligand and that intravenous immunoglobulin therapy is useful in blocking this mechanism with resultant survival benefits. Further studies have since proven these theories to be incorrect. This short review describes the key advances in the terminology, classification, causality and treatment of EN, and identifies future priorities and challenges in the understanding and management of this condition.     

In the pursuit of classifying severe cutaneous adverse reactions

We suggest adding an additional type of lesion to the existing 4 types of lesions of the erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), namely "flat typical target" and call the original typical targets "raised typical target." The EM group would consist of raised typical targets and raised atypical targets, similar to the original definition, and the SJS/TEN group would consist of flat typical targets, flat atypical targets and macules with or without blisters. In our proposed modified classification (Table 1), all the lesions that are found in the EM group are raised, whereas all lesions that characterize the SJS/TEN group are flat, even though they have blisters on them.     

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.     

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.     

Severe Stevens‐Johnson syndrome/toxic epidermal necrolysis overlap syndrome—beyond skin involvement

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but serious dermatologic diseases with many potential multisystem complications. We describe the case of an 8‐year‐old girl who developed severe SJS/TEN overlap syndrome (25% of her body surface area was affected) complicated by pancreatitis and bronchiolitis obliterans. These rare complications emphasize the need for careful, intensive monitoring of possible complications and an interdisciplinary team approach to provide optimal treatment and follow‐up.     

Stevens-Johnson syndrome induced by doxycycline

Stevens-Johnson syndrome (SJS) is an acute mucocutaneous eruption nosologically related to erythema multiforme (EM) and toxic epidermal necrolysis (TEN). Medications are the most common triggering factors for SJS, with anticonvulsants, sulfonamides, penicillins, allopurinol, and nonsteroidal anti-inflammatory drugs (NSAIDs) most commonly implicated. SJS is very rarely associated with tetracyclines. We report a case of doxycycline-induced SJS in a 46-year-old man.     

Successful treatment of interstitial lung disease related to Stevens–Johnson syndrome/toxic epidermal necrolysis overlap with etanercept: A case report and published work review

Interstitial lung disease (ILD) is a rare complication of Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). In this study, we present the case of a 33‐year‐old woman who was diagnosed with ILD related to SJS/TEN overlap syndrome. Surprisingly, the patient did not respond to combination therapy with steroids and i.v. immunoglobulin, but rapidly improved after two doses of etanercept treatment. To our knowledge, this is the first case of SJS/TEN‐induced ILD that was successfully treated with etanercept. We reviewed another two cases of ILD associated with SJS/TEN, and found that unlike the other cases, in the present case, ILD occurred early in the course of the disease and rapidly improved after etanercept injection. We discovered that in the present patient, the serum interleukin‐6 level increased during the progressive stage and declined after the initiation of treatment with etanercept.     

Expression of cytokines and chemokine receptors in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis

BACKGROUND: Erythema multiforme (EM) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are caused by a dysregulation of cellular immunity. OBJECTIVES: To evaluate further the potential role of certain cytokines and chemokine receptors in cutaneous lesions of patients affected by EM and SJS/TEN and to establish whether such diseases are polarized preferentially towards a T-helper (Th) 1 or Th2 pattern. METHODS: Biopsy specimens from eight patients with EM, six with SJS/TEN and three healthy controls were stained for immunohistochemical examination using the alkaline phosphatase-antialkaline phosphatase method. The monoclonal antibodies used included those to tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-2, IL-5, IL-13, receptor 3 for C-C chemokines (CCR3), receptor 3 for C-x-C chemokines (CXCR3) and CXCR4. RESULTS: The SJS/TEN specimens showed significantly higher expression of all the cytokines and chemokine receptors (except CXCR3) tested than the EM specimens. Both lesional series showed significantly higher expression of all the receptors tested than the healthy control specimens, with the sole exception of a lower expression of CCR3 in EM specimens. Comparison between molecules associated with a Th1 or Th2 response revealed a predominance of Th1 response in EM and no significant imbalance between Th1 and Th2 in SJS/TEN. CONCLUSIONS: We have provided further evidence that TNF-alpha is strongly expressed in SJS/TEN lesions and therefore it may be involved in the epidermal necrosis featured in such diseases. IFN-gamma may play an important role both in EM and SJS/TEN. IL-2, IL-5 and IL-13 may contribute to the cutaneous immunoinflammation in these diseases. Chemokine receptors may be involved strongly in the recruitment of inflammatory cells in lesional skin. In our cases we found a sharp polarization towards a Th1 pattern in EM, while the SJS/TEN lesions showed a mixed Th1/Th2 pattern.     

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.     

Nonpigmenting fixed drug eruption as a possible abortive variant of toxic epidermal necrolysis: immunohistochemical and serum cytokine analyses

Nonpigmenting fixed drug eruption (NPFDE) is clinically indistinguishable from Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) in its initial presentation. The traditional paradigm that epidermal changes are absent in NPFDE cannot be easily reconciled with the clinical resemblance to SJS/TEN. We therefore investigated whether NPFDE is pathogenetically different from pigmented FDE (PFDE) or SJS/TEN and which factors are responsible for the lack of hyperpigmentation. NPFDE lesions before challenge were characterized by larger numbers of CD8+ intraepidermal T cells associated with a paucity of melanocytes, compared with those in PFDE. Very high levels of serum interleukin (IL)‐10 were noted after clinical challenge. We conclude that NPFDE is a clinical syndrome with heterogeneous histological expression. NPFDE with epidermal involvement may be an abortive form of SJS/TEN, in which progression to TEN can be prevented by IL‐10.     

Stevens-Johnson syndrome and toxic epidermal necrolysis overlap in a patient receiving cetuximab and radiotherapy for head and neck cancer

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe and life-threatening adverse drug reactions. Herein we report about a patient with head and neck cancer, who developed SJS-TEN overlap after having received cetuximab and radiotherapy. To date, there are only two reports of TEN associated with cetuximab therapy in patients with cancer. Every skin condition in a patient with cancer leading to extensive exfoliation of the skin should alert the oncologist of a possibility of drug-induced SJS or TEN.     

Toxic epidermal necrolysis induced by phenytoin and whole brain radiotherapy

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been associated with some drugs, particularly anticonvulsants such as phenytoin. Some authors have pointed out an increased risk of TEN/SJS when phenytoin is associated with whole brain radiotherapy. We report a patient diagnosed with breast adenocarcinoma and brain metastases that was on treatment with phenytoin and, shortly after receiving whole brain radiotherapy, developed toxic epidermal necrolysis.     

Anti-desmoplakin antibodies in erythema multiforme and Stevens-Johnson syndrome sera: pathogenic or epiphenomenon?

The pathophysiology of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) is unclear. Whether autoantibodies against desmoplakin (Dp) I and II play a pathogenic role or result from an epitope spreading phenomenon is uncertain. Our aim was to characterize the keratinocyte antigens recognized in EM, TEN and SJS. Of 33 patients studied, 2 had TEN, 1 SJS, 9 EM major and 21 EM minor, according to Roujeau's criteria. All sera were studied by indirect immunofluorescence (IIF), immunoblotting and immunoprecipitation. Twenty normal sera were used as controls. 10/33 sera reacted with polypeptides of 215 and/or 250-kDa molecular mass, which co-migrate with Dp I and II as assessed by an anti-Dp I and II monoclonal antibody on IB. In IP, none of the anti-Dp I and -Dp II 10 patient sera immunoprecipitated Dp I and/or II from radiolabeled keratinocyte extracts. Two of 10 patient sera (SJS, EM minor) reacted with DpI and II when denaturated by the IB procedure. The reactivity against intracellular antigens DpI and II as denaturated proteins may result from the epidermal damage produced by aggressive autoreactive T cells, playing therefore only a secondary role in the pathogenesis of the disease.     

A patch testing and cross‐sensitivity study of carbamazepine‐induced severe cutaneous adverse drug reactions

Background The usefulness of the drug patch testing for Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is still controversial. Recent studies have shown that HLA‐B*1502 is strongly associated with CBZ‐SJS/TEN in Chinese and Southeast Asian populations. Objective To evaluate the usefulness of patch tests for patients with carbamazepine (CBZ)‐induced SJS, TEN and drug reaction with eosinophilia and systemic symptoms (DRESS) and the cross‐reactivity in patch tests among the aromatic antiepileptic drugs. Methods We measure the frequency of positive patch test reactions and cross‐sensitivity to structure‐related aromatic anti‐epileptic drugs (AEDs) for patients after SJS/TEN or DRESS episodes caused by CBZ. CBZ and other structure‐related AEDs used for patch testing were prepared in 10% and 30% petrolatum. Secondary measures included the association of HLA‐B*1502 genotype and frequency of possible side effects from the patch tests. Results Positive patch test reactions to 30% CBZ in the CBZ‐SJS/TEN were 62.5% (10/16), and 70% (7/10) in the CBZ‐DRESS. None of the 10 healthy controls displayed a positive reaction to tested agents. Cross‐sensitivity to other aromatic AEDs was observed in both the CBZ‐SJS/TEN and the CBZ‐DRESS. Only the HLA‐B*1502 genotype was present and strongly associated with the CBZ‐SJS/TEN, but not with the CBZ‐DRESS. Conclusion Drug patch testing is a safe and useful method for the identification of CBZ as the culprit drug of SJS/TEN as well as DRESS. Testing of chemically or pharmacologically related AEDs may provide information on cross‐reactivity for these patients.     

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.     

Severe flucloxacillin‐induced acute generalized exanthematous pustulosis (AGEP), with toxic epidermal necrolysis (TEN)‐like features: does overlap between AGEP and TEN exist? Clinical report and review of the literature

Acute generalized exanthematous pustulosis (AGEP) and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse drug reactions. Especially in TEN, large areas of the skin and mucosae may become detached. Although AGEP and SJS/TEN are distinct entities with a different clinical picture, pathogenesis, prognosis and treatment, they may share some features, raising the hypothesis of overlap between both entities. We present a severe case of AGEP, caused by flucloxacillin, clinically presenting with TEN‐like features and pronounced systemic symptoms with haemodynamic and respiratory instability. Furthermore, we present a review of the literature on cases of AGEP with features resembling SJS/TEN or a supposed overlap with SJS/TEN.