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.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

Possible involvement of CD14+ CD16+ monocyte lineage cells in the epidermal damage of Stevens-Johnson syndrome and toxic epidermal necrolysis

Background Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are characterized by keratinocyte apoptosis and necrosis, resulting in epidermal detachment. Although monocytes abundantly infiltrate the epidermis in SJS/TEN skin lesions, the properties and functions of these cells have not been fully examined. Objectives To determine the properties of monocytes infiltrating into the epidermis in SJS/TEN. Methods Immunostaining of skin sections was performed to examine the membrane markers of monocytes infiltrating into skin lesions. Results Immunostaining of cryosections from 11 SJS/TEN skin lesions revealed numerous CD14+ monocytes located along the dermoepidermal junction and throughout the epidermis. The cells coexpressed CD16, CD11c and HLA‐DR. CD14+ CD16+ cells were identified in very early lesions without epidermal damage, suggesting that their infiltration is a cause, rather than a result, of epidermal damage. Moreover, these cells expressed CD80, CD86 and CD137 ligand, indicative of their ability to facilitate the proliferation and cytotoxicity of CD8+ T cells. CD16+ cells infiltrating the epidermis and detected at the dermoepidermal junction were immunostained and counted in paraffin‐embedded skin sections obtained from 47 patients with drug rash manifested as TEN, SJS, maculopapular‐type rash or erythema multiform‐type rash. The number of CD16+ monocytes infiltrating the epidermis increased significantly, depending on the grade of epidermal damage. Conclusions These findings suggest that the appearance of CD14+ CD16+ cells of monocyte lineage plays an important role in the epidermal damage associated with SJS/TEN, most probably by enhancing the cytotoxicity of CD8+ T cells.     

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.     

Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are majorly (65-75%) induced by a variety of drugs. SJS/TEN could be recognized as SCARs or drug immune reactions, if the reactions are elicited by drugs. The recent studies suggested that SJS/TEN is a specific immune reaction initiated by the cytotoxic T lymphocytes (CTLs) via human leukocyte antigens (HLAs)-restricted pathway. The patho-mechanism involving HLA-restricted presentation of a drug or its metabolites for T-cell activation is supported by the findings of strong genetic associations with HLA alleles (e.g. HLA-B*15:02 and carbamazepine-SJS/TEN, and HLA-B*58:01 and allopurinol-SJS/TEN). However, the genetic associations of SJS/TEN or drug induced cutaneous immune reactions are complex, which are drug specific and ethnicity specific. The genetic polymorphisms and diversity of HLA alleles may provide different binding affinities for drug antigens to launch the activation of specific CTLs responses, further leading to the unique clinical manifestations in SJS/TEN. Fas-FasL and perforin/granzyme B have been advocated mediating the epidermal necrosis in SJS/TEN. Our recent study showed that granulysin, a cytotoxic protein produced by CTLs or natural killer (NK) cells, is the key mediator for disseminated keratinocyte death in SJS/TEN. From the point of view of a physician, the profounder understanding of the genetic predisposition and patho-mechanism we discover, the better strategies for prevention, clinical management, and therapeutic methods of SJS/TEN we can develop in the near future.     

Diagnosis and management of Stevens-Johnson syndrome/toxic epidermal necrolysis

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare, immunologically mediated cutaneous adverse reaction characterized by mucous membrane and epidermal detachment, with a mortality ranging from 15% to 25%. Risk factors for the development of SJS/TEN include immune dysregulation, active malignancy, and genetic predisposition. Medications are the most common cause, particularly antimicrobials, antiepileptics, allopurinol, and nonsteroidal anti-inflammatory medications. Drug-specific CD8 T-cells and natural killer cells are thought to be the major inducers of keratinocyte apoptosis via release of soluble cytotoxic mediators, including Fas ligand, perforin/granzyme, tumor necrosis factor, and granulysin. When SJS/TEN is suspected clinically, appropriate therapy should be instituted without delay. All patients should be managed initially in an intensive care unit or burn unit under a multidisciplinary team of physicians experienced in the care of patients with SJS/TEN. Available data support the use of various pharmacologic agents to halt disease progression and improve outcomes, but no single drug has been found to be superior or beneficial for all patients. Future research should focus on developing a better understanding of the genetic susceptibility and immunopathophysiology of the disease, as well as novel diagnostic and therapeutic targets to improve patient outcomes.     

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.     

Toxic epidermal necrolysis: current evidence, practical management and future directions

Toxic epidermal necrolysis (TEN) is a rare disorder characterized by extensive epidermal death. Almost all cases appear to be caused by an idiosyncratic drug reaction. Proposed pathogenic mechanisms are conflicting, and the evidence for the benefits of individual treatments is inadequate, and in some cases contradictory. The mortality rate remains high. We review the literature pertaining to the pathogenesis of TEN and drug reactions in general. The rationale for therapeutic interventions, together with reported evidence of efficacy, are considered. We present a composite model of TEN, based on previous work and suggested pathogeneses of TEN, mechanisms of drug reactions and reported cytotoxic lymphocyte (CTL) cytolytic pathways. In this system, TEN, like some other cutaneous drug eruptions, is an HLA class I-restricted, specific drug sensitivity, resulting in clonal expansion of CD8+ CTLs. Cytotoxicity is mediated by CTL granzyme and possibly death receptor (DR) ligand (DR-L), probably Fas ligand (FasL). Particular to TEN, there is then an amplification sequence involving further DR-L expression. FasL is likely to be particularly important but tumour necrosis factor (TNF) may well contribute, via the TNF receptor 1 (TNF-R1) death pathway. Alternatively, we suggest the possibility of upregulation of an antiapoptotic TNF-R1-nuclear factor kappaB pathway, which would proscribe treatments which downregulate this pathway. None of the published data on individual treatment efficacies is sufficiently strong to suggest a definitive single treatment. Currently a multifaceted regimen appears indicated, targeting various likely intermediary mechanisms, including elimination of residual drug, immunosuppression, inhibition of DR pathways, general antiapoptotic strategies, and aggressive supportive care. Particular attention has been directed at avoiding potential conflicts between different treatments and avoiding agents that theoretically might have a net proapoptotic rather than antiapoptotic effect. Nursing on a specialized unit is of paramount importance.     

Toxic epidermal necrolysis and Stevens-Johnson syndrome: soluble Fas ligand involvement in the pathomechanisms of these diseases

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are considered part of a spectrum of adverse cutaneous drug reactions showing severe and extensive skin detachment. TEN and SJS are morphologically characterized by active apoptotic keratinocyte cell death that results in the separation of the epidermis from the dermis. TEN is a life-threatening disease with a high mortality rate (20-30%). Although several therapies have been tried, there is no specific outstanding of generally accepted treatment for TEN at present. The pathogeneses of TEN and SJS have not yet been fully elucidated. We have demonstrated that high concentrations of soluble FasL (sFasL) are detected in TEN/SJS patients' serum samples and sFasL secreted by peripheral blood mononuclear cells interacts with the Fas expressed on diseased keratinocytes in TEN/SJS. Our data suggested sFasL is a prime candidate for therapeutic intervention, whereas a few recent papers have reported sFasL levels were not elevated in some TEN patients. An urgent review of the pathophysiology in TEN/SJS is needed to resolve this issue and to determine more effective treatment regimes.     

Severe cutaneous adverse drug reactions

The clinical manifestations of drug eruptions can range from mild maculopapular exanthema to severe cutaneous adverse drug reactions (SCAR), including drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which are rare but occasionally fatal. Some pathogens may induce skin reactions mimicking SCAR. There are several models to explain the interaction of human leukocyte antigen (HLA), drug and T‐cell receptor (TCR): (i) the “hapten/prohapten” theory; (ii) the “p‐i concept”; (iii) the “altered peptide repertoire”; and (iv) the “altered TCR repertoire”. The checkpoints of molecular mechanisms of SCAR include specific drug antigens interacting with the specific HLA loci (e.g. HLA‐B*15:02 for carbamazepine‐induced SJS/TEN and HLA‐B*58:01 for allopurinol‐induced SCAR), involvement of specific TCR, induction of T‐cell‐mediated responses (e.g. granulysin, Fas ligand, perforin/granzyme B and T‐helper 1/2‐associated cytokines) and cell death mechanism (e.g. miR‐18a‐5p‐induced apoptosis; annexin A1 and formyl peptide receptor 1‐induced necroptosis in keratinocytes). In addition to immune mechanism, metabolism has been found to play a role in the pathogenesis of SCAR, such as recent findings of strong association of CYP2C9*3 with phenytoin‐induced SCAR and impaired renal function with allopurinol SCAR. With a better understanding of the mechanisms, effective therapeutics and prevention for SCAR can be improved.     

Stevens–Johnson syndrome and toxic epidermal necrolysis due to anticonvulsants share certain clinical and laboratory features with drug‐induced hypersensitivity syndrome,despite differences in cutaneous presentations

Background. Drug‐induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by late disease onset, fever, rash, hepatic dysfunction, haematological abnormalities, lymphadenopathy and often, human herpesvirus (HHV) reactivation. The diagnosis of DIHS is based on the combined presence of these findings. Anticonvulsants are a major cause of DIHS and may also cause Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We examined whether SJS/TEN due to anticonvulsants display similar clinical and laboratory features seen in DIHS. Methods. Patients diagnosed with SJS or TEN due to anticonvulsants (n = 8) were examined and their clinical features and laboratory findings were compared with patients with anticonvulsant‐related DIHS (n = 6). Results. Seven of the eight patients with SJS/TEN developed symptoms > 3 weeks after starting anticonvulsants. Hepatic dysfunction was present in six patients with SJS/TEN and five patients with DIHS. Leucocytosis and/or eosinophilia was noted in seven patients with SJS/TEN and four patients with DIHS. Only one patient in the SJS/TEN group had atypical lymphocytosis; this was present in four patients with DIHS. Reactivation of HHV‐6 was detected in one of the four patients tested in the SJS/TEN group, although it was seen in five of the six patients with DIHS. Conclusions. TSJS/TEN due to anticonvulsants may exhibit some clinical and laboratory features of DIHS. The nature of the cutaneous involvement should be emphasized in the diagnosis of DIHS.