Recent developments in the research of Stevens-Johnson syndrome and toxic epidermal necrolysis: pathogenesis, diagnosis and treatment

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe disorders affecting the skin and mucous membranes, identified by low incidence but high mortality rates. Medications, particularly antibiotics, are the most common causative agents, and infection is also considered a common pathogenic factor. Multiple alleles diagnosed with drug allergies, which can help in predicting the occurrence of SJS and TEN were detected during research. Although the pathogenesis of SJS and TEN is not yet fully understood, the current gold standard for treatment involves early diagnosis and treatment, discontinuation of the allergenic drugs, and supportive care. Treatment options include systemic use of corticosteroids, intravenous immunoglobulin, cyclosporine A, plasmapheresis, and TNF-α inhibitors.

Background

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions (ADRs) characterized by significant necrosis and skin and mucous membrane detachment. SJS was first reported in 1922 by American pediatricians Albert Mason Stevens and Frank Chambliss Johnson, while TEN was described by Alan Lyell in 1956 [1, 2]. Currently, SJS and TEN are classified as varying degrees of the same disease, differentiated by the extent of epidermal detachment: SJS involves less than 10% of the body surface area, TEN involves more than 30%, and intermediate cases are classified as SJS/TEN overlap [3, 4].

The typical primary lesions of SJS/TEN present as an acute onset of widespread painful macules and flat atypical target lesions with central blistering reminiscent of erythema multiforme that rapidly coalesce, resulting in extensive epidermal detachment. A positive Nikolsky sign, which indicates dislodgement of the upper layers from the lower layers of the epidermis, can be elicited by apply ing lateral pressure in the perilesional skin, affected skin or normal skin. Mucosal erosion is observed in > 90% of patients [5].

The pathogenesis of SJS/TEN is not yet fully understood, but clinical and histopathological studies indicate that they are types of delayed hypersensitivity reactions primarily triggered by drugs (95%) [6]. Infections represent the second major cause. Common clinical triggers include antibacterial, antiepileptic, antipyretic analgesics, antigout medications, biologics, and traditional Chinese medicines, with pathogens like Mycoplasma and herpes simplex virus also being implicated. Recent advances in pharmacogenomics have identified multiple alleles associated with drug allergies [7]. SJS/TEN are rare, with an incidence rate of approximately 5.76 cases per million person-years, and the incidence is about twice as high in Asian and African populations compared to Caucasians, with no significant gender differences. The highest risk is observed in children aged 1 to 10 years and patients over 80 years old [8]. These conditions lead to severe complications like infections, sepsis, gastrointestinal bleeding, and multiple organ failure syndrome, contributing to a high mortality risk [9–11]. Recent reports indicate a mortality rate of about 11% in France [12]. SJS and TEN, as dermatological emergencies, have a high mortality rate. The underlying biological mechanisms of their pathogenesis are not fully understood, and there are no standardized treatment protocols. In recent years, there has been an increasing number of reports of SJS/TEN induced by various new drugs, with more severe conditions and challenging treatment. Early diagnosis and active, effective treatment are crucial for improving patient outcomes.

This narrative review aims to provide a comprehensive overview of the recent developments in the research of SJS and TEN. The literature search was conducted using PubMed, Web of Science, and Embase. Keywords and MeSH terms used included “Stevens-Johnson Syndrome,” “Toxic Epidermal Necrolysis,” “pathogenesis,” “diagnosis,” “treatment,” and “biomarkers.” The inclusion criteria were: (1) peer-reviewed articles published in English; (2) studies focusing on SJS/TEN, including clinical trials, cohort studies, case series, and reviews; (3) articles published within the last 10 years. The exclusion criteria were: (1) non-English articles; (2) articles not directly related to SJS/TEN; (3) articles with insufficient data or unclear methodology. Due to the limited number of studies on SJS/TEN, some seminal works published earlier were also included to provide a comprehensive overview.

Pathogenesis and risk factors of SJS/TEN

Immune-induced apoptosis mechanism

Current clinical and histopathological studies indicate that SJS and TEN are primarily caused by drug stimuli, resulting in a T-cell mediated type IV hypersensitivity reaction. Drugs or their metabolites are processed and presented to cytotoxic T lymphocytes which activate four main pathways mediated by cytotoxic T lymphocytes and natural killer (NK) cells. These pathways include interactions between granzyme, Fas and its ligand (Fas ligand, FasL), perforin-granzyme B, and the IL-15 mediated pathway, leading to apoptosis of keratinocytes and extensive epidermal necrolysis [13].

Recent studies have indicated that systemic and skin-restricted delayed-type drug hypersensitivity reactions are associated with distinct resident and recruited T cell subpopulations. Skin-resident memory T cells (TRM) and recruited T cell subsets play a significant role in the pathogenesis of severe systemic dermatological conditions, such as Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) [14].

Granzyme is a cytolytic protein produced and secreted by cytotoxic T cells and NK cells [15]. It can induce apoptosis of target cells by the caspase pathway. Studies have shown that the levels of Granzyme in the blister fluid of SJS/TEN patients are significantly elevated, with concentrations two to four orders of magnitude higher than those of other cytotoxic proteins such as perforin, granzyme B, or soluble Fas ligand. This elevation in Granzyme levels is specific to SJS/TEN patients and is positively correlated with disease severity. Additionally, the addition of Granzyme to keratinocyte cultures induces apoptosis, highlighting its role in promoting cell death [16]. The blister fluid of SJS/TEN patients is rich in various cytokines and inflammatory mediators, reflecting the intense local immune response. Among them, tumor necrosis factor-alpha (TNF-α) is identified as a potential biomarker of disease severity. TNF-α, a pro-inflammatory cytokine, plays a crucial role in mediating inflammation and apoptosis. Its elevated levels in blister fluid are closely associated with the extensive epidermal necrosis and mucosal damage observed in SJS/TEN [17]. Recent studies have further highlighted the role of tumor necrosis factor-alpha (TNF-α) in SJS/TEN pathogenesis. TNF-α levels in blister fluid and serum are significantly elevated in acute-phase patients and correlate with the extent of epidermal detachment and mortality risk. Additionally, interleukin-6 (IL-6) and interferon-gamma (IFN-γ) are enriched in blister fluid, reflecting their contribution to cytotoxic T cell activation and systemic inflammation [18]. These cytokines may synergistically amplify keratinocyte apoptosis through the JAK-STAT signaling pathway, as evidenced by in vitro models.

Animal experiments have demonstrated that granzyme can cause widespread epidermal detachment. The interaction of Fas/FasL factor-related apoptosis ligands is another crucial mechanism potentially inducing SJS/TEN. Fas undergoes a conformational change in the intracellular death domain, recruiting a large number of Fas-associated death domain proteins as adaptor proteins, which initiates a cascade reaction wherein proteases gradually dissolve the cell from the inside, ultimately causing cell apoptosis.

Recent research has further elucidated the role of type 1 innate lymphoid cells (ILC1 s) in the early immune response, particularly in amplifying the inflammatory environment through the production of cytokines such as IFN-γ. Additionally, alarmins (e.g., HMGB1, S100 proteins) and death ligands (e.g., TNF, FasL, TRAIL) are critical in initiating and propagating the immune response. Annexin A1, a protein involved in regulating inflammation and apoptosis, has also been implicated in the pathogenesis of SJS/TEN.

Cell death in SJS/TEN occurs through multiple mechanisms, including cytotoxic granule-associated programmed cell death, apoptosis, and necroptosis. Necroptosis, a form of programmed necrosis mediated by RIPK1, RIPK3, and MLKL, has been shown to play a significant role in keratinocyte death, particularly when apoptosis is inhibited. These diverse cell death pathways interact to drive the extensive tissue damage observed in SJS/TEN, highlighting the complexity of its pathogenesis.

Drug HLA susceptibility genes

Multiple human leukocyte antigen (HLA) alleles can increase the risk of SJS and TEN as demonstrated by recent studies [19]. These HLA-associated occurrences of SJS/TEN exhibit significant racial and genetic predisposition specificity. For instance, Asian patients have a higher risk of drug-induced SJS/TEN, particularly with antiepileptic drugs and compound cold medicines. HLA alleles associated with SJS/TEN can serve as pharmacogenomic biomarkers to guide treatment in patients, including: HLA-A*0206, HLA-B*44:03, HLA-C*07:01, HLA-DRB1*08:03, HLA-DRB1*12:02, HLA-A*02:06 [20] (related to nonsteroidal anti-inflammatory drugs), HLA-B*5801 (related to allopurinol), HLA-B75, HLA-B*1508, HLA-B*1511, HLA-B*1518, HLA-A*3101 (related to carbamazepine), HLA-B*1502 (related to oxcarbazepine, carbamazepine, lamotrigine), and HLA-B*5101 (related to phenobarbital) [13, 19, 21–27]. The ongoing development of pharmacogenomic studies and the continuous discovery of susceptibility factors may represent a breakthrough in the future diagnosis and treatment of SJS/TEN and other types of drug eruptions.

Immune checkpoint inhibitors and anticancer drugs

Immune checkpoint inhibitors (ICIs) eradicate tumor cells by activating cytotoxic T lymphocytes. ICIs include monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed death receptor 1 (PD-1), and programmed death ligand 1 (PD-L1). However, ICIs can cause immune-related adverse events affecting multiple systems and organs, with a notable propensity for causing immune-related skin reactions [28–30]. These skin reactions associated with PD-1 inhibitors include nonspecific rashes, itching, vitiligo, lichenoid dermatitis, psoriasis, bullous pemphigoid, sarcoidosis, alopecia, and severe skin reactions like SJS and TEN [31, 32]. The precise mechanism by which ICIs cause SJS/TEN remains unclear. It is hypothesized that ICIs may block antigens co-expressed by tumor cells and at the epidermal-dermal junction or other skin layers, disrupting T cell homeostasis in the skin. This disruption results in cytotoxic and inflammatory reactions in the skin and mucous membranes, where drug-specific CD8 + cytotoxic T cells accumulate, ultimately leading to extensive apoptosis of keratinocytes [33, 34]. As the use of ICIs in cancer treatment increased, the number of ICI-induced SJS/TEN cases have also risen [35–39]. Reports of ICIs causing SJS/TEN include cases associated with nivolumab, ipilimumab, and pembrolizumab [37, 40, 41].

Infection

Studies indicate that infections can exacerbate or initiate drug reactions like SJS and TEN. Infections with human herpesvirus (HHV)−6, Epstein-Barr virus (EBV), Mycoplasma pneumoniae, and COVID-19 have all been associated with the onset and progression of SJS/TEN [42, 43]. Reports indicate that infections like Mycoplasma pneumoniae and COVID-19 can directly cause SJS/TEN [44, 45]. The proposed mechanism involves infections inducing the expression of co-stimulatory molecules (CD80, CD86, and HLA molecules), with viral infections stimulating the immune system to enhance the antigen-presenting the drug presentation process of cells [46].

Diagnosis of SJS/TEN

Biomarkers for early diagnosis of SJS/TEN

Cytokines involved in the pathogenesis of SJS and TEN, like galectin-7, receptor-interacting protein 3 (RIP3), and nonspecific biomarkers including granzyme, chemokine ligand 27 (CCL-27), and soluble apoptosis-related ligands, serve as significant biomarkers for the early diagnosis of these conditions. An abnormal increase in these cytokines can indicate the onset of SJS/TEN. Galectin-7, primarily expressed in stratified squamous epithelium, is involved in cell apoptosis, proliferation, and differentiation, and can be overexpressed in apoptotic keratinocytes. Studies have indicated that peripheral blood mononuclear cells from SJS/TEN survivors, when exposed in vitro to drugs that induce SJS/TEN, exhibit a significant increase in galectin-7 levels. These levels correlate with disease severity, with acute phase levels significantly increasing and gradually decreasing during later stages of disease development [47]. RIP3 is associated with programmed necrosis, and necrotic keratinocytes in patients with SJS/TEN who release significant amounts of RIP3 into the bloodstream. Serum levels of RIP3 correlate with the detachment area and severity of SJS/TEN [48]. Granzyme, which induces apoptosis in keratinocytes, increases the serum levels in patients with SJS/TEN before skin detachment and mucosal involvement occurs, making it a crucial marker for early diagnosis [49]. Cutaneous T cell-attracting chemokine (CTACK), also known as CCL-27, is a small molecular weight cytokine in the CC chemokine family. IL-1β or TNF-α can stimulate the overexpression of CCL-27, which recruits T cells to inflamed skin areas and participates in the pathogenesis of SJS/TEN. Acute phase SJS/TEN patients have significantly increased levels of CCL-27 in their skin as indicated by studies [50]. However, the elevation of granzyme and CCL-27 also occurs in various other skin diseases, which limits the specificity and thus the diagnostic value of these markers in SJS/TEN. IL-15 not only maintains the activity of cytotoxic cells but also induces the production of TNF, and its serum levels significantly correlate with disease severity and higher in-hospital mortality of SJS/TEN [51, 52].

Determining the association between medications and SJS/TEN

Identifying medications that cause SJS/TEN is crucial for early diagnosis and treatment of the disease. The primary methods for identifying allergenic drugs currently include patch testing, the Lymphocyte Transformation Test (LTT), and the Enzyme-Linked Immunospot (ELISpot) assay for cytokine detection [53–55]. Considering the significant role of T lymphocytes in the pathogenesis of SJS/TEN, the LTT is a principal method for identifying allergenic drugs, especially during the convalescent phase of the disease to confirm the causative agents. Additionally, new technologies such as the IFN-γ ELISpot and microarrays enable the detection and analysis of various cytokines and chemokines involved in the acute phase of TEN [56, 57].

Currently, the Naranjo score and the ALDEN score are commonly used in clinical settings to assess the causal relationship between suspected drugs and SJS or TEN [58, 59]. The Naranjo score is a generic tool used to correlate drug reactions with adverse reactions, while the ALDEN score is specifically designed to identify the causative factors for SJS/TEN.

The Naranjo score, proposed by Canadian pharmacologist Naranjo, is widely used to assess and determine the correlation and closeness between drug use and adverse drug reactions (ADRs). This scoring system consists of 10 medical questions related to ADRs; each assigned a specific score. After tallying the scores, the correlation is categorized into four levels: (≤ 0), possible (1–4), probable (5–8), and definite (≥ 9).

The ALDEN score is specifically designed for SJS/TEN and has been validated using data from the SCAR (Severe Cutaneous Adverse Reaction) EuroSCAR case–control studies. This scoring system incorporates a drug risk database developed from EuroSCAR study results, providing higher reliability compared to the Naranjo score.

Treatment of SJS/TEN

Assessment of SJS/TEN severity

SJS and TEN pose a high mortality risk, particularly for elderly patients and children, making the objective assessment of SJS/TEN severity, especially mortality risk, critically important for treatment.

The SCORTEN (severity-of-illness score for TEN) is a widely used scoring system designed to assess the severity of SJS/TEN and predict the mortality of patients who are hospitalized [60]. This scoring system includes seven independent prognostic factors related to disease prognosis and has demonstrated good predictive ability. The predicted mortality rates by SCORTEN align closely with actual mortality rates as indicated by numerous studies. However, some scholars have raised concerns about the accuracy of predictions and the inclusion of additional prognostic factors [9, 61]. SCORTEN assessments are required within 24 h of admission, but some studies propose that assessments conducted three days after admission may yield more accurate predictions [62]. As clinical diagnosis and treatment techniques for SJS/TEN have evolved, the mortality rate has gradually decreased compared to when SCORTEN was established, leading to cases where SCORTEN predicts higher mortality rates than those observed clinically [63]. A retrospective analysis has revealed that in pediatric patients with SJS/TEN, the SCORTEN prediction of mortality has been significantly overstated compared to the actual mortality rate [64].

SCORTEN does not include age, race, or gender in its scoring, and recent studies indicate that there may be additional independent prognostic factors that significantly impact the prognosis of SJS/TEN [65, 66].

The ABCD-10 (age, bicarbonate, cancer, dialysis, 10% BSA) scoring system, introduced in 2019, builds on the SCORTEN system by incorporating age criteria, adding dialysis treatment as an indicator, and increasing the weight of malignant tumors. This system has demonstrated good discrimination and calibration capabilities [67]. However, group studies in patients diagnosed with SJS/TEN from multiple countries have revealed that the ABCD-10 scoring system does not exhibit better predictive performance compared to SCORTEN. Both SCORTEN and ABCD-10 face challenges in finely assessing the severity of SJS/TEN [68, 69]. Also, in clinical settings, SJS/TEN often coexists with underlying diseases, and the sample sizes are not sufficient to support the inclusion of more effective prognostic factors, posing challenges to enhancing these scoring systems.

In recent years, researchers have attempted to validate potential prognostic indicators for SJS/TEN using more clinical data-based parameters. The neutrophil-to-lymphocyte ratio (NLR) has been associated with disease activity in various dermatological conditions. A retrospective study has shown a correlation between NLR and SCORTEN in SJS/TEN patients, but a large-sample study is needed to further clarify its direct relationship with prognosis. Similarly, the correlation between the systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR), and SCORTEN as well as patient prognosis has been confirmed by a retrospective study, but the association between these indicators and the occurrence of patient death events requires validation from large-sample studies [70, 71].

Early management of SJS/TEN

Inappropriate and untimely early management of SJS and TEN can lead to disease progression and worse, thereby increasing the mortality risk. Therefore, along with promptly establishing a clear diagnosis for patients undergoing SJS/TEN, early and active treatment is essential. Patients should discontinue suspected causative drugs at the earliest stages of the disease, remove themselves from the causative environment and factors, and if the drugs triggering SJS/TEN cannot be definitively identified, all medications should be stopped. Reducing the duration of exposure to the causative drug can effectively lower the mortality rate and reduce the symptoms of SJS/TEN.

Early management of SJS/TEN also includes monitoring and maintaining vital signs, ensuring effective circulatory volume, maintaining electrolyte balance, and providing skin wound care to minimize detachment. During fever reduction and wound care, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and sulfonamide antibiotics should be avoided.

Systemic treatment of SJS/TEN

Due to the low incidence rate of SJS and TEN, significant individual variability among patients, and the incomplete understanding of its pathogenesis, there is a lack of large-sample randomized controlled trials for medications. Consequently, systemic treatment plans for SJS/TEN remain contentious. Based on previous reports, systemic treatments for SJS/TEN primarily include the use of corticosteroids, intravenous immunoglobulin (IVIG), and cyclosporine. Tumor necrosis factor (TNF) inhibitors are emerging as a new area of study, and plasmapheresis has also indicated efficacy in some patients.

Corticosteroids

Corticosteroids suppress immune-active cells and reduce the inflammatory response mediated by factors like interleukins and tumor necrosis factor-alpha (TNF-α). They exhibit anti-inflammatory and immunosuppressive effects, can reduce the apoptosis of keratinocytes, and enhance skin symptoms caused by SJS and TEN [72]. Traditionally, corticosteroids have been used in the clinical treatment of SJS/TEN for an extended period. Clinically, early and high-dose corticosteroid pulse therapy is often used, and some studies indicate that this approach is effective in reducing mortality rates. However, there is still lack of support from large-sample clinical trial data. Also, high doses of corticosteroids may exacerbate infections and cause gastrointestinal ulcers and bleeding.

Intravenous immunoglobulin (IVIG)

Intravenous immunoglobulin (IVIG) has both immunoreplacement and immunomodulatory functions. It can regulate and block Fc receptors, reducing antibody synthesis. IVIG contains Fas, which can inhibit Fas-FasL binding, thereby suppressing Fas-FasL mediated apoptosis of keratinocytes and prevent the progression of SJS and TEN [73]. However, some studies indicate that combining corticosteroids with IVIG does not offer a significant advantage over the use of corticosteroids by itself, in preventing mortality. Also, the mortality rate of patients undergoing SJS/TEN treated solely with IVIG did not significantly differ from the SCORTEN-predicted mortality rates of untreated patients [74]. This indicates that the value of IVIG in the treatment of SJS/TEN remains controversial and underscores the need for support from large-sample clinical trials.

Cyclosporine

Cyclosporine is a calcineurin inhibitor that acts on lymphocytes and inhibits the synthesis and release of lymphokines. It suppresses drug-induced Fas-L expression and TNF-α secretion, thus providing effective treatment for SJS and TEN [75]. Cyclosporine A administered at a dose of 3–5 mg/kg/day for 7–10 days can significantly reduce the mortality rate of patients undergoing SJS/TEN as indicated by studies [76]. However, other studies indicate that the mortality rate of patients treated solely with cyclosporine A does not significantly differ from those receiving only symptomatic supportive care [77].

Tumor necrosis factor inhibitor

TNF inhibitors competitively inhibit the effects of TNF-α, thereby suppressing epithelial cell apoptosis, delaying epidermal detachment, and inducing epithelial regeneration [74]. International reports have assessed the use of TNF-α antagonists to treat SJS and TEN in recent years. Commonly used TNF-α inhibitors include etanercept, infliximab, adalimumab, and golimumab. Some small-sample clinical studies have indicated that TNF-α antagonists can shorten the course of SJS and TEN and reduce the mortality rate of patients, especially those with severe cases [78–82]. However, there is currently a lack of large-scale clinical studies on these drugs, and their safety and efficacy still need further validation. A recent prospective observational study has shown that compared to the use of corticosteroids alone, the combination therapy with TNF-α antagonists can significantly promote re-epithelialization, reduce the use of corticosteroids, and decrease the acute mortality rate in irEN patients without increasing major adverse events. This combined medication approach offers a potential new method for the treatment of SJS/TEN [83].

Plasmapheresis

Plasmapheresis can reduce the concentration of immune complexes and various inflammatory mediators in the body of the patient. Theoretically, it can accelerate the clearance of these immune complexes, thereby reducing the severity and duration of the disease. However, this treatment method has only been reported in isolated cases and lacks large-scale clinical evidence, so its effectiveness still needs further verification.

Other treatment modalities and therapeutic targets for SJS/TEN

PC111 is a human monoclonal antibody currently under development by the startup company PinCell srl, primarily indicated for the treatment of pemphigus. Research suggests that the Fas/FasL system is crucial to the underlying mechanisms of SJS/TEN, and PC111, by blocking FasL, represents a potential therapeutic strategy for SJS/TEN [84].

A recent study has highlighted the potential of JAK-STAT inhibitors in the treatment of SJS/TEN. Targeted inhibition with the pan-JAK inhibitor tofacitinib in vitro reduced keratinocyte-directed cytotoxicity. In vivo oral administration of tofacitinib, baricitinib or the JAK1-specific inhibitors abrocitinib or upadacitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN.This study uncovers the JAK/STAT and interferon signalling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAKi as a curative therapy [85].

Preliminary clinical trials have demonstrated a favorable response to this therapeutic approach. Research indicates that the NLRP3 inflammasome plays a key role in the pathogenesis of Stevens Johnson Syndrome/Toxic Epidermal Necrolysis and may be associated with the severity of skin detachment and ocular surface disease, making chemical inhibitors related to it a potential new direction for SJS/TEN treatment [18]. The treatment modalities and level of evidence were shown in the Table 1.

Table 1.

Summary of treatment modalities and levels of evidence

Treatment modality	Level of evidence	Description
Corticosteroids	Expert opinion/case series	Used for their anti-inflammatory and immunosuppressive effects; limited by lack of large-scale trials
Intravenous immunoglobulin (IVIG)	Expert opinion/case series	Immunomodulatory effects; efficacy remains controversial
Cyclosporine	Expert opinion/case series	Calcineurin inhibitor; some studies show reduced mortality, but results are inconsistent
TNF-α inhibitors	Expert opinion/small studies	Emerging therapy with potential benefits; requires further validation
Plasmapheresis	Case reports	Limited evidence from isolated case reports
Other therapies	Expert opinion	Including JAK inhibitors, PC111, etc., with preliminary

Management of SJS/TEN complications

During the acute phase of SJS and TEN, various complications can arise, like infections, multi-organ involvement extending beyond the skin, hypoproteinemia, anemia, shock, and electrolyte imbalances. Effectively controlling these complications is crucial for reducing mortality rates associated with SJS/TEN. Managing complications in SJS/TEN requires a multidisciplinary collaborative treatment approach.

Infection

Patients with SJS and TEN experience extensive detachment of skin and mucous membranes, severely compromising the skin barrier function and rendering them highly susceptible to various infections. These infections can significantly increase the mortality rate of patients with SJS/TEN [86]. While skin infections are the most common, infections of mucosally-involved sites like the gastrointestinal tract, respiratory tract, and urogenital tract are also prevalent. The most frequent pathogens in SJS/TEN infections include Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae, with methicillin-resistant Staphylococcus aureus (MRSA) being a primary cause of severe lung infections and bacteremia, likely attributable to its primary role as a pathogen in skin infections [87].

The prophylactic use of antibiotics in SJS/TEN treatment may increase the mortality risk of patients, possibly due to antibiotic-induced bacterial resistance and the exacerbation of SJS/TEN by certain antibiotic classes [88]. Therefore, in the treatment of SJS/TEN, careful consideration of the type and timing of antibiotics is crucial. It is essential to avoid drugs like sulfonamides, which could increase the risk of exacerbating SJS/TEN.

Visceral damage and management

Common visceral injuries in patients with SJS and TEN encompass damage to the lungs, kidneys, and liver, with approximately 40% incidence of lung and respiratory system involvement, 50% for liver, and 20.8% for kidneys. Severe visceral damage significantly increases the mortality risk [89]. In cases where patients undergoing SJS/TEN present bronchial lesions, respiratory distress, hypoxemia, and lung infections, acute respiratory distress may necessitate active assessment for potential tracheal intubation and mechanical ventilation. Various factors like sepsis, medications (e.g., allopurinol, nonsteroidal anti-inflammatory drugs, antibiotics), a history of chronic kidney disease, and hypoproteinemia pose risks for acute renal failure in patients with SJS/TEN.

Management of patients with acute renal failure or high-risk involves early discontinuation of nephrotoxic drugs, controlling infections, maintaining fluid, electrolyte, and acid–base balance, providing nutritional support, and conducting renal replacement therapy if necessary. Approximately 5% of patients having SJS/TEN with acute renal failure may eventually require long-term dialysis treatment. Liver involvement represents the most common visceral damage in these patients. Even after controlling skin symptoms, liver function may continue to deteriorate, often indicated by a persistent increase in liver enzyme levels without a concurrent rise in bilirubin. Increased bilirubin levels typically signify a poor prognosis. Initial management of liver involvement entails discontinuation of hepatotoxic drugs and, when required, administration of hepatoprotective medication. However, concurrent use of multiple hepatoprotective medications is not advised due to the potential exacerbation or induction of SJS/TEN by some drugs. These patients may also experience a rare and fatal complication induced by medications: acute vanishing bile duct syndrome (VBDS), characterized by cholangitis, bile duct destruction, and resulting in cholestasis. Nonsteroidal anti-inflammatory drugs, antibiotics, and carbamazepine can cause this complication [90]. Presently, there is no specific treatment for VBDS; however, hepatoprotective medication and immune treatment may offer partial effectiveness, with case reports indicating the use of TNF-α inhibitors and/or plasmapheresis [91]. This complication is rare, rapidly progressing, and associated with a poor prognosis, with effective treatment methods necessitating further validation with larger sample sizes. Other complications in SJS/TEN encompass gastrointestinal mucosal involvement leading to bleeding and ulcers, as well as impacts on the nervous system and myocarditis.

Ocular involvement and treatment

Literature indicates that between 50 and 88% of patients having SJS and TEN experience complications affecting the cornea, conjunctiva, and eyelid, potentially resulting in permanent vision loss due to corneal scarring or neovascularization. However, the severity and occurrence of these eye-related complications do not directly correlate with the overall severity and mortality risk of SJS/TEN [92]. Studies indicate that nonsteroidal anti-inflammatory drugs and cold medicines are closely associated with severe ocular involvement in SJS/TEN, and patients diagnosed with TEN having a higher likelihood of ocular involvement than patients with SJS. However, there is no significant difference between the two in the incidence of severe ocular complications and sequelae [93]. Currently, there is no standardized treatment for ocular involvement in SJS/TEN. Symptomatic treatments like lubricants, antibiotic eye drops like quinolones, and hormonal therapies are commonly used. Due to potential ocular sequelae during and after recovery from SJS/TEN, long-term monitoring of ocular health in these patients is advisable [94].

Limitations

This review also has some limitations. Firstly, the document may primarily cite studies from specific regions or populations, which could limit the generalizability of the research findings. Patients of different races, ages and genders may respond differently to treatments for SJS/TEN, thus necessitating a more diverse sample to enhance the representativeness of the study. Secondly, some of the treatment methods mentioned in the review may be based on lower levels of evidence, such as case reports or small studies, which could affect the strength and reliability of treatment recommendations. Thirdly, the article may lack an in-depth analysis of the impact on patients’ long-term prognosis and quality of life. The treatment of SJS/TEN should not only focus on the management of the acute phase but also consider long-term health status and quality of life.

We believe that future research should include a broader range of geographical regions and diverse populations to ensure that the research results better reflect the needs of the global patient population. Additionally, more rigorously designed, large-sample randomized controlled trials are needed to validate the effectiveness and safety of existing treatment methods, including long-term follow-ups to assess the durability of treatment effects, patients’ survival quality and potential late-onset complications. Exploring new treatment strategies, we will continue to monitor emerging treatment methods, such as biologics and targeted therapies and their potential applications in the treatment of SJS/TEN, aiming to provide more theoretical foundations for clinical practice.

Conclusion

SJS and TEN represent rare, life-threatening, severe skin and mucosal reactions primarily triggered by medications. They are characterized by rapid progression, extensive skin lesions, and severe systemic symptoms, posing a significant threat to life. Cytokine-mediated immune responses play a key role in the pathophysiology of these reactions. Early diagnosis is critical for effective management of SJS/TEN, and various drug-related scoring systems prove invaluable for identifying potential triggers. Currently, treatment approaches for this condition lack standardization supported by large-sample clinical data. Therapeutic options like corticosteroids, IVIG, cyclosporine, plasmapheresis, and TNF-α inhibitors have demonstrated some effectiveness. Given the potential for long-term multisystem complications, a multidisciplinary approach to both diagnosis and treatment of SJS/TEN is essential for optimizing patient outcomes.

Abbreviations

SJS

Stevens-Johnson syndrome

TEN

Toxic epidermal necrolysis

ADRs

Adverse drug reactions

Fas

Factor-related apoptosis

FasL

Fas ligand

TNF

Tumor necrosis factor

HLA

Human leukocyte antigen

ICI

Immune check point inhibitor

CTLA-4

Cytotoxic T lymphocyte-associated antigen-4

PD-1

Programmed cell death protein 1

PD-L1

Programmed cell death 1 ligand 1

HHV

Human herpes virus

EBV

EB virus

RIP3

Receptor-interacting protein 3

CTACK

Cutaneous T cell-attracting chemokine

SCAR

Severe cutaneous adverse reaction

SCORTEN

Severity-of-illness score for TEN

10%BSA

ABCD-10 age, bicarbonate, cancer, dialysis

IVIG

Intravenous immunoglobulin

VBDS

Vanishing bile duct syndrome

Author contributions

Conception and design of the research: Limin Yao; Xiaoqing Du Acquisition of data: Liling Liu, Xiaoqing Du, Xia Su, Yanning Qi, Ran Ma, Bo Wei Analysis and interpretation of the data: Bo Wei, Xiaoqing Du, Xia Su, Ran Ma Obtaining financing: Limin Yao, Xiaoqing Du Writing of the manuscript: Xiaoqing Du, Limin Yao, Liling Liu Critical revision of the manuscript for intellectual content: Yanning Qi, Limin Yao, Xiaoqing Du. All authors read and approved the final draft.

Funding

The Medical Science Research Project of Hebei Province (No. 20241336,20231294).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.