A Systematic Review of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Epidemiology and Treatment Strategies

A uncommon toxic skin condition called toxic epidermal necrolysis is characterized by extensive epidermal detachment and necrosis. It is typically accompanied by fatigue, fever, chills, myalgia, fluid and electrolyte disorders, and problems involving several organs. According to reports, the global mortality rate for TEN and SJS ranges from 10% to 34%.¹ Based on the stripped surface area, this illness may be categorized into three groups. Body surface area was less than 10% in patients with Stevens-Johnson syndrome (SJS), the intermediate type is overlapping SJS-TEN (with epidermal detachment covering 10% to 30% of body surface area), and greater than 30% in those with TEN. The fundamental distinction between SJS and TEN, two toxic skin diseases with rare but life-threatening, is the magnitude of the epidermal stripping region and the problems that result. The high mortality rate of TEN is often associated with factors such as fluid loss due to extensive epidermal detachment, severe systemic infection and toxic symptoms, and multi-organ dysfunction, among which sepsis-induced multi-system organ failure represents the most common cause of death in TEN.² In the early clinical stages, TEN lacks specific manifestations, with reactions typically being mild. The onset and progression of lesions often require one week or longer, compounded by the absence of standardized diagnostic criteria or consensus for TEN, which hinders timely and accurate diagnosis in patients.³ Although numerous treatment modalities exist, their efficacy remains controversial, and standardized treatment guidelines have yet to be established. These factors contribute to the clinical challenges in managing TEN, resulting in its high mortality rate and poor prognosis.⁴

With continuous advancements in medical technology, significant progress has been made in recent years regarding the diagnosis of TEN, management of its clinical manifestations, identification of pathogenesis, and identification of high-risk populations. However, the mortality rate of TEN remains persistently high, imposing substantial burdens on patients and society. The unclear pathogenesis of TEN and the lack of universally accepted diagnostic methods have led to considerable therapeutic challenges.³ Although numerous studies have demonstrated that factors such as age, gender, comorbidities, and medication use are risk factors for both onset and mortality in TEN, existing research still exhibits multiple limitations.⁵ Moreover, large-scale epidemiological surveys and risk factor analyses of TEN remain insufficient in China. Therefore, conducting epidemiological investigations of TEN and analyzing mortality-related risk factors will provide valuable insights and guidance for therapeutic strategies.

Epidemiological Features of Toxic Epidermal Necrolysis

According to some studies, the annual incidence of SJS and TEN, a rare cutaneous adverse reaction, is roughly 0.94 to 9.2 cases per million people.⁶ The US hospitalization records from 2009 to 2012 indicated that the incidence of SJS was 8.61 to 9.69 visits per million people, with the SJS/TEN ratio being 1.46–1.84 times and the TEN ratio being 1.58–2.26 times.⁷ According to the American Association of Dermatology Hospitals’ 2020 TEN-related standards, there are between 1.6 and 9.2 SJS/TEN patients per million annually in the US.⁸ There is a growing tendency in the number of TEN. The inadequate method of determining patient data may be the cause of this increase,⁹ and the true incidence of SJS and TEN may be influenced by factors such as medicines, genetic background, HIV, TB, cancer, and regional variations.¹⁰ The frequency of TEN has increased in recent years due to the rise in therapeutic medications and their associated side effects. The occurrence of TEN is also impacted by the rise of cancer and other underlying diseases in the current environment. The mortality rate of TEN (about 30%) is at least six times higher than that of SJS (<5%), with infection and multiple organ failure being the primary causes of death.¹¹ Due to varying degrees of therapy and pathogenic variables, the mortality and prevalence rates of TEN may vary across institutions and geographical areas.¹²

Risk Factors

TEN may have some influence on the incidence and mortality of TEN because it is an uncommon skin peeling illness. Thus, a deeper comprehension of the pertinent risk factors for TEN will aid in our investigation of the condition and offer pertinent recommendations for additional research.

Environmental Factor

The findings should not be disregarded, even though environmental factors have less of an effect than the preceding causes on the rise in TEN incidence and death. A seasonal tendency in the overall number of SJS and TEN toward spring was indicated by a retrospective review of the medical records of 50 patients at the Barnes-Jewish hospital between 1995 and 2007. Compared to other seasons, the number of TEN cases (53%) rose dramatically in the spring. The percentage of SJS/TEN cases did not vary by season, despite the fact that infection rates were high in the spring. Consequently, we discovered that the incidence of SJS and TEN may be linked to infection, and that as the risk of infection rises with the seasons, so will the prevalence of SJS and TEN. This is particularly true during seasons with relatively high temperature and environmental fluctuations.

Age

Older persons are far more likely than younger adults to develop SJS/TEN, particularly drug-related SJS/TEN, and to experience increased short- and long-term morbidity and death. Age has a significant impact on the prognosis survival rate of TEN patients and is a risk factor for the condition. Patients over 65 have a survival rate of less than 30%, whereas patients under 65 have an 82% survival rate. Younger patients have a far greater survival rate than older patients. In contrast to children, who have a lower SJS/TEN mortality rate than adults, senior patients may have a larger percentage of medication usage and a mix of numerous underlying disorders. TEN and SJS are uncommon childhood illnesses that have a 7.5% estimated fatality rate. However, children are more prone than adults to experience issues related to the mucosa in many affected populations. The median proportion of skin detachment was 20% of the body surface, and mucosal lesions were present in 95% of the TEN children. The majority of children with TEN are susceptible to related mucosal lesions, mostly because their skin is not yet fully developed as a barrier and they are less resilient to adults.¹³

Sex

According to the current study, SJS/TEN is more common in female patients than in male patients, with an incidence ranging from 52% to 68%. Pregnant women, particularly those who are also HIV or HIV-tuberculosis coinfection, are particularly at risk for SJS/TEN because of their drug use. Two epidemiological studies conducted in France and Germany reported a male to female ratio of 0.6, and further data supported the idea that the TEN ratio varied between 0.5 and 0.7. In fact, the majority of adverse medication reactions include a similar female predominance. For example, if normalized to the number of drugs received, age, diagnosis, and survival, the frequency of drug use is 35% higher among women than among men.² However, these demographics have changed in recent years, with a slight increase in men, as more men now have HIV and AIDS. As a result, the SJS/TEN may also show a higher male predominance. The increased number of medications used¹¹ that AIDS patients get and the changed ratio of CD4 + to CD8 + T cells may be the causes of their 1000-fold higher risk compared to healthy individuals.

Disease Factors

TEN mortality was 15% in the other groups and 60% in patients undergoing anti-tuberculosis treatment. Anti-TB medications are widely used in underdeveloped nations like India. Therefore, low-income countries have a higher prevalence of TEN linked to anti-TB medications.⁶ In addition to immunosuppressive conditions like bone marrow transplantation, HIV infection, connective tissue disease, and malignant tumors (leukemia, lymphoma, and solid tumor),¹⁴ TEN is linked to infectious diseases like herpes virus, Mycoplasma pneumoniae, and hepatitis A virus, as well as non-communicable diseases like collagen vascular disease and radiation therapy.¹⁵ Patients with systemic lupus erythematosus, bone marrow transplant recipients, and particularly those with AIDS are at increased risk. The association between SJS/TEN and HIV was validated by a multicentric study conducted in sub-Saharan Africa, a region with a high incidence of HIV. The study also found a correlation between SJS/TEN and a high frequency of antiretroviral treatment usage.¹⁶ It might be directly linked to the potential aberrant pattern of detoxification and/or drug metabolite generation brought on by the disease itself, as well as the immune system’s malfunction following HIV infection.

Due to its inherent epidermal defects, TEN/SJS increased the rate of infection, which in turn raised the death rate, and loss of skin barrier function. The mortality rate and the extent of mononuclear cell infiltration in the dermis were highly correlated. Patients with mild, moderate, and severe skin infiltration had respective death rates of 27%, 53%, and 71%. The prolongs re-epithelialization and affects TEN healing by hyperbilirubinemia, which will also lengthen the reepithelialization period. In patients with hyperbilirubinemia, the time it takes to restore epithelialization is prolonged to 9 weeks or more, and even after treatment, it still takes 4–5 weeks for the epithelium to repair. Initially, this process takes 2–3 weeks. This study revealed that bilirubin partially slows the epithelialization process, that there is a correlation between epithelialization and liver function, and that re-epithelialization and TEN healing may be facilitated by plasma exchange and human albumin therapy.

The most frequent cause of death in TEN is sepsis-induced multisystem organ failure. Sepsis was linked to the majority of deaths, and high-dose steroids were used to treat the majority. Microangiopathy and a diminished capacity to heal skin tissues are two consequences of hyperglycemia that raise the risk of ulcers and skin infections. Hyperglycemia may have an indirect impact on the course or recovery of TEN by impairing the function of the skin barrier, which could delay wound healing or exacerbate secondary infection, even though the primary pathogenic mechanism of TEN is epidermal cell death. Since there are numerous factors that can influence serum glucose, more research is still necessary to confirm the link between serum glucose and TEN.¹⁷

Drug Factors

Similar to the acute rejection of transplantation, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe lesions of the acute destructive process of the skin and mucosal epithelium brought on by a strong immune response.¹⁸ Drugs are typically the cause of this reaction, with 70% to 90% of instances showing a drug link. Although it is now believed that over 100 distinct medicines can induce TEN, the bulk of cases are caused by a small number of substances. The most frequent cause of TEN/SJS was antiepileptic medications (60%) followed by antibiotics (26.6%) and other medications, including chemotherapeutic and nonsteroidal anti-inflammatory medicines.¹⁹ Carbamazepine was the most often prescribed antiepileptic medication, followed by levetiracetam, phenytoin, and phenobarbital. Erythromycin, cefotaxime, trimethoprim, cloxacillin, and amoxicillin were among the antibiotic medication group.²⁰ According to estimates, the first three weeks of medication administration and the first eight weeks of therapy are when the increased risk of medication as a primary contributor triggering TEN in the general population typically occurs. The first week is typically when most drug users are at the biggest risk for SJS and TEN.^21,22

Antimicrobial Drugs

With a weekly incidence of 4.5 cases per million, antimicrobial sulfonamides are most strongly linked to this illness. Reactive metabolites act as haptens by attaching to carrier proteins on the epidermal cell membrane and triggering an immune response. Sulfonamide-induced TEN patients are typically slowly acetylated, primarily exhibiting an increase in sulfonamide metabolism that is partially guided by the alternative pathway of cytochrome P-450 oxidation, which results in increased hydroxylamine production.²³ Additionally, there is proof that genetic variations in a patient’s metabolic reactions to sulfonamides are linked to the development of TEN.⁹ The increased illness in TEN patients may be caused by abnormalities in the detoxification of reactive metabolites in sulfonamide-induced TEN patients and first-degree relatives.²⁴ Drugs have a significant effect on adults, but the effects are considerably more pronounced for kids. The majority of data point to anti-infective sulfonamides as a significant independent risk factor for SJS/TEN in children among the highly suspected medications. Anti-infective sulfonamides are the most often implicated agents in SJS/TEN in the general population, and they are frequently thought to occur in children.²⁵ Aminopenicillins, quinolones, cephalosporins, tetracyclines, and imidazole antifungals were among the non-sulfonamide antibiotics that were substantially linked to the illness.²⁰ Drug cross-reactivity may result in recurrent TEN that is deadly. There is a chance that penicillins and cephalosporins will interact.^15,26

Anticonvulsant Drugs

Anticonvulsants are frequently used to treat childhood epilepsy, however they can also result in non-immediate t-cell-mediated skin side effects that can be fatal, including toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS). Aromatic anticonvulsants, including carbamazepine, phenytoin, and phenobarbital, are among the most frequent causes of SJS/TEN in children. Additionally, the findings of connected research revealed that four extremely dubious medications, including carbamazepine and phenobarbital, were found in children. In Han Chinese, Chung et al¹⁰ found a high association between HLA-B * 1502, SJS, and carbamazepine, as well as HLA, drug allergy, and ethnic background. Egunsola et al²⁰ discovered in a retrospective research that valproic acid (VPA) raised the risk of SJS/TEN in pediatric patients receiving lamotrigine (LTG).²⁷ Because VPA prevents hepatic glucuronidation, LTG metabolism and plasma levels are decreased. Children’s medications should therefore be more careful and precise than those for adults, and they should be evaluated from a variety of angles.²⁸

NSAID

Oxicam derivatives have been found to be strongly linked to disease among NSAIDs,²⁹ and tenoxicam (TMX) was the most common pathogenic medication in a research of 50 TEN patients. We identified papers showing that acetaminophen may potentially cause TEN with severe skin peeling,³⁰ despite the fact that there is a weak correlation between the two.³¹ Although oxiam NSAIDs, such as piroxicam, have been found to be significant risk factors in the general population, pertinent research has revealed that no pediatric exposure has been reported to these medications because they are typically not prescribed to children younger than 15, making it challenging to verify the association.³²

Allopurinol

SJS/TEN can be brought on by the uric acid-lowering medication allopurinol. HLA-B * 1501 was discovered to be linked to allopurinol-induced TEN. The length of medication and the number of hospitalizations will also have an impact on the etiology of TEN, in addition to the drug’s mechanism of action. Consequently, it is very crucial to review the history of medications.

Genetics and Immunology of Related Drugs

Studies have found that HLA-B*1502 is closely associated with carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), while HLA-B*5801 is strongly correlated with allopurinol-induced SJS/TEN.³³ Similar associations have been confirmed across different populations. In the Han Chinese population, allopurinol exhibits significant association with HLA-B.³⁴ Anticonvulsants such as allopurinol and carbamazepine are primary precipitating agents for SJS/TEN13; additionally, other cited causative agents include cold medications, nonsteroidal anti-inflammatory drugs (NSAIDs), and multi-ingredient medications.³⁵ Reports indicate that cold medication-associated Stevens-Johnson syndrome (CM-SJS/TEN) with severe mucosal involvement (SMI), including serious ocular complications, shows significant association with HLA-A and HLA-B in Japanese subjects, whereas this HLA genotype is unrelated to CM-SJS/TEN cases without SMI.³⁵ Therefore, genetic susceptibility, including HLA genotypes, may differ between SJS/TEN patients with and without SMI.³⁵ Studies have reported significant associations between HLA-B and CM-SJS/TEN with SMI in India and Brazil. Carbamazepine-induced SJS/TEN is associated with HLA-B* or HLA-A*while allopurinol-induced SJS/TEN is linked to HLA-B.³⁶ HLA analysis suggests that genetic susceptibility plays a role in drug-induced disease responses. Carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is closely associated with HLA-B alleles in Taiwanese Han patients.³⁷ HLA-A alleles are strongly correlated with carbamazepine-induced SJS/TEN in Japan and Europe, while HLA-B alleles show significant association with carbamazepine-induced SJS/TEN in European patients.³⁸ Allopurinol-induced SJS/TEN is closely linked to HLA-B.

Vaccine, Mycoplasma, Herpesvirus Factors

We also came to the conclusion that, in addition to SJS/TEN, vaccinations, mycoplasma, herpes viruses, including the SARS-CoV-2 (COVID-19) that has been circulating recently, may also cause SJS/TEN based on other relevant accounts. According to recent findings, vaccinations may cause SJS or TEN.³⁹ Although there appears to be a link between vaccination and SJS and TEN, the reported number was quite low in comparison to the high number of vaccinations, and the advantages of vaccination outweighed the possible risks of SJS and TEN, according to the results of the vaccine adverse event reporting system.¹⁰ Adult SJS/TEN is rarely caused by Mycoplasma, and the taxonomy and classification of mycoplasma-induced skin eruptions are difficult. However, there is still debate regarding the criteria used to classify mycoplasma as SJS or TEN.⁴⁰ A real-time PCR and lymphocyte transformation assay were utilized to confirm that TEN was also caused by a herpesvirus infection.⁴¹ Steroids and etanercept were effective treatments for this patient.⁴² Furthermore, research conducted in the wake of the 2019 COVID-19 outbreak revealed that the incidence of SJS/TEN rose following COVID-19 infection and that COVID-19 increased mortality in SJS/TEN patients. Given that 57–95% of hospitalized COVID-19 patients received antibiotic treatment, one explanation for these findings may be virus-induced drug allergy, which has been suggested in other viral infections assuming several antibiotics are associated with SJS/TEN. However, more research is required to elucidate any mechanisms underlying the association between COVID-19 and SJS/TEN.⁴³

Epidermal Peeling Size

The likelihood of death and the difficulties of curing a patient increase with the size of the patient with detached BSA. According to research by Boorboor P et al, TEN mortality was significantly correlated with skin and mucosal shedding, depending on the premorbid state and the extent of body surface area involved (TBSA). However, the average was 40%, and the primary causes of death were metabolic disturbances following sepsis and loss of skin barrier function.⁴⁴ As mean age grew, so did the mean degree of skin separation. The largest study report identified 315 SJS patients, including 39.9% of women,⁴⁵ with the percentage of women believed to be between 33% and 62%. Mortality rates ranged from 25% to 100% when the stripped region reached the majority of the body surface. The infection can happen at any point during the TEN process since the epidermal peeling results in a significant loss of bodily fluids and the loss of the skin’s protective layer. In order to prevent protein loss and encourage the healing of skin lesions, active nutritional support should be initiated as soon as possible. During the first few days, fluid must be restored by veins and protect the epidermis that has not yet been shed. Treatment that partially inhibits the process of epithelial apoptosis is crucial in the early stages of TEN because the degree of epidermal detachment is a significant prognostic factor in TEN patients.⁴⁶

TEN Diagnostic Method-SCORTEN

Toxic epidermal necrolysis (TEN) is a severe, life-threatening toxic skin disorder that not only causes extensive epidermal desquamation but also leads to increased mortality due to subsequent complications. Early diagnosis of TEN plays a decisive role in enabling proactive supportive care and therapeutic interventions. Therefore, accurate and timely diagnosis is critical for the management and treatment outcomes of TEN.

Bastuji-Garin et al⁴⁷ developed a seven-point checklist for disease severity scoring, specifically designed for TEN cases, known as SCORTEN, which has been proven accurate in predicting mortality rates. The checklist includes age, presence of malignancy, affected body surface area, heart rate, serum urea, bicarbonate, and glucose levels. SCORTEN is based on seven clinical and laboratory risk factors, ranging from 0 to 7, with higher scores indicating increased mortality risk. In addition to these seven factors, the severity of skin mononuclear infiltration assessed by histology is considered predictive of survival in TEN patients. SCORTEN has been demonstrated as a disease severity score that accurately predicts survival in SJS, TEN, or SJS/TEN patients.

However, increasing clinical studies in recent years have indicated that SCORTEN scores may overestimate or underestimate patient mortality rates.⁴⁸ In 2012, Qin-yuan Zhu et al⁴⁹ validated seven mortality risk factors in the SCORTEN score using relevant patient clinical data metrics, but found that the applicability of this analytical method to Asian countries remains uncertain and its validity requires further evaluation. Notably, the mortality factors analyzed in this study were similar to the seven factors in SCORTEN and did not incorporate new mortality risk predictors, highlighting certain limitations. In 2025, Stewart et al⁵⁰ highlighted that SCORTEN scores and existing prognostic models have yet to incorporate novel mortality-related predictive indicators.

TEN Therapeutic Tool

When a patient is diagnosed with TEN, he must immediately stop using the relevant pathogenic drugs, treat them promptly, and closely monitor any changes in his condition. Based on the results of previous research, TEN typically begins to epithelialize after two to three weeks of lesions. Therefore, the main focus of future research will be on how to treat TEN in a way that will speed up its reepithelialization and promote the wound surface’s rapid healing. Supportive therapy, systemic corticosteroids, high-dose intravenous immunoglobulin (IVIG), plasma exchange (PE) therapy, anti-TNF-α biological agents, surgery, etc. are currently used as clinical treatments for TEN. However, each treatment mechanism is unique, the results vary, and the effectiveness of these treatments has not been established in large randomized trials. Additionally, some of the studies have produced controversial findings. Therefore, we should keep researching TEN treatment in order to increase patient prognosis and cure rate, given the disagreement around these therapeutic effects and the lack of conventional treatment standards at the moment.

Medication

There is not a standard treatment for TEN at the moment. Therefore, finding a treatment medicine that is more effective and has fewer side effects remains a challenging task given the current clinical condition.

Immunoglobulins (IVIG)

IVIG is believed to work against Fas by means of autoantibodies. By preventing FasL from attaching to the Fas receptor, IVIG therapy disrupts downstream signaling cascades. This therapeutic strategy is founded on the theory of the FasL-Fas interaction. Furthermore, intravenous immunoglobulin efficiently inhibits recombinant FasL-mediated cell death by inhibiting Fas, which causes keratinocyte apoptosis in vitro. Even while data from in vitro research appears to support IVIG’s efficacy, there is a claim that IVIG treatment lowers the disease’s death rate. Some studies, however, take the opposite stance. Bachot et al’s prospective non-comparative trial demonstrated that IVIG treatment had a nephrotoxic effects, did not lower mortality or slow the progression of the disease, and that other particular treatments were not allowed for elderly or renal failing patients. Furthermore, it is challenging to compare these trials since patients and treatment plans varied greatly, with each patient having a unique dose schedule (Table 1). IVIG may be helpful for TEN, according to the data, however the majority of the results are contradictory, and the benefits of IVIG in lowering mortality have been minimal. As a result, there is disagreement over the benefits and drawbacks of treating TEN. Currently, some academics and medical professionals employ pertinent medications based on their personal experiences and the conditions of their patients.

Table 1 Demonstration of IVIG Treatment Effects in Different Studies

Immunization Therapy

In order to minimize cytotoxicity and apoptosis on the skin and mucosal surfaces, immunomodulatory or inhibitory therapy aims to decrease the activity of activated T lymphocytes and cytokines while lowering granprotease at the cellular level. A single 5 mg/kg infliximab infusion stopped skin shedding and caused the detached skin to reepithelialize quickly, removing any active or erosive lesions from the skin. A polypeptide called cyclosporine A (CsA) prevents the production of interleukin-2 (IL-2), which in turn prevents IL-2-induced CD4 + and CD8 + t-cell infiltration and NK cell activation. CsA is an effective treatment approach because SJS/TEN involves keratinocyte apoptosis mediated by t-cells and natural killer cells. CsA lowers mortality in patients with SJS/TEN and slows the acute phase progression of systemic epidermal detachment. However, the systemic use of CsA can cause some adverse reactions, including nausea, headache, hyperlipidemia, hypertension, renal dysfunction, etc. Cyclosporin as an immunosuppressant may increase the risk of lymphoma and other malignancies, and cyclosporin therapy should be avoided in SJS / TEN patients with active hematologic malignancies or AIDS.⁶⁰

Treatment with Corticoids

Some specialists think that the use of glucocorticoids has significantly slowed the disease’s course, notwithstanding the contentious early use of glucocorticoid shock therapy. Some specialists, however, contend that high dosages of glucocorticoids are more infectious due to their ability to suppress lymphocytes and damage skin and mucosal tissue, and that early glucocorticoid shock therapy has no effect on the stable phase of the disease or the period needed for reepithelialization. Additionally, corticoids can worsen or slow the healing of wounds, raise the risk of infection, and increase the frequency of bleeding in the gastrointestinal tract. Corticosteroids should not be used in the regimen of patients with TEN because, according to related reports, the risk of systemic steroid use far outweighs its benefits once a large area of dermis loss (20–60%) occurs. A study conducted in the United States revealed²³ that some patients receiving corticosteroid treatment had poor prognoses, and that after stopping steroid treatment, the mortality rate for severe TEN decreased from 66% to 33%. The drug is also one of the factors contributing to TEN mortality. Immunoglobulin and glucocorticoids are currently a frequent early-stage medication in clinical treatment that can successfully postpone the onset of the illness. While cyclosporine by itself was not helpful for survival, the combination of cyclosporine and glucocorticoids greatly enhanced the prognosis and quality of survival. In order to improve the cure rate and prognostic effect of patients, the majority of SJS/TEN patients appear to require a multimodal treatment regimen that includes various intermediate mechanisms, including immunosuppression, inhibition of the Fas pathway, removal of residual drugs, general antiapoptotic strategies, and active supportive therapy.

Antibiotic Therapy

Infection is the primary cause of mortality in TEN, and rational antibiotic use is a critical factor in reducing mortality rates.⁷ However, current mainstream guidelines and studies do not recommend routine systemic prophylactic antibiotic use.⁶¹ A retrospective cohort study demonstrated that routine prophylactic antibiotics not only failed to reduce the incidence of sepsis but also significantly increased the risk of drug-resistant bacterial infections and superinfections. The study explicitly stated that short-term targeted prophylaxis covering Staphylococcus aureus and Gram-negative bacteria should only be administered to high-risk patients with SCORTEN scores ≥3, epidermal exfoliation areas>50%, or concurrent immunocompromised status.

Therapeutic use constitutes the cornerstone of TEN infection management. Once infection is confirmed or sepsis is highly suspected, broad-spectrum antibiotics should be initiated immediately.⁶² A multicenter observational study demonstrated that initiating effective antibiotic therapy within 24 hours after TEN diagnosis reduced the 28-day mortality rate from 41.2% to 17.8%. The study emphasized that the initial regimen must cover Staphylococcus aureus (including MRSA), Pseudomonas aeruginosa, and Enterobacteriaceae, with piperacillin-tazobactam or carbapenems as first-line agents, followed by step-down therapy upon bacterial culture results.⁶³ Additionally, the 2021 European Society of Intensive Care Medicine guidelines supplemented that topical chlorhexidine or silver preparations may be applied to local wounds for antimicrobial purposes, but sulfonamides should be avoided to prevent exacerbation of the condition.⁶² Therefore, TEN antibiotic use must adhere to the principles of “non-routine prophylaxis, early diagnosis and treatment, and precise step-down therapy.” The accurate and rational use of antibiotics is a critical component of comprehensive TEN management, with both prophylactic and therapeutic applications strictly guided by evidence-based medicine to avoid risks of drug resistance and secondary infections due to misuse.

Plasma Exchange

The purpose of plasma exchange (PE) is to rid the body of toxins, immunological complexes, autoantibodies, drug metabolites, etc., in order to reduce the severity of the illness and shorten its duration. By eliminating a tiny portion of soluble apoptosis-inducing factors from serum, this treatment is most likely to completely eradicate fas-mediated keratinocyte death. According to B et al, 101 out of 13 TEN patients recovered completely after PE treatment. After beginning steroid therapy, plasmapheresis may be a useful treatment for refractory TEN. The mortality rate before and after plasmapheresis sharply dropped from 23.5% (2000–2006) to 5.6% (2007–2013) in a retrospective study of 3510 patients in two Japanese university hospitals during.2000–2013⁶⁴ However, prospective randomized studies are required to elucidate the efficacy of PE on TEN, as the therapeutic mechanism and effect of PE remain unclear at this time.

JAK Inhibitor Treat

According to recent research, the JAK/STAT signaling system is a key cause of keratinocyte toxicity, epidermal shedding, and skin inflammation. Of tissue immune cells, macrophages exhibit the strongest inflammatory response. One of the main causes of TEN is the activation of the JAK/STAT pathway. Nordmann et al discovered that TEN signaling activates STAT 1, and TEN patients’ skin invading immune cells and keratinocytes have high levels of STAT 1 phosphorylation. The identification of JAK/STAT as a therapeutic target and the possibility of targeting JAKi as a therapeutic approach are both explained by the upregulation of JAK/STAT signaling in immune cells and keratinocytes, which may cause extensive tissue damage in TEN through a potentially harmful self-amplified inflammatory cascade.⁶⁵

By achieving in vitro focused inhibition, JAKi inhibitors improve clinical and histological disease severity and recovery time while lowering keratinocyte-directed cytotoxicity, keratinocyte death, and immune cell infiltration. Seven TEN patients had significantly decreased skin phosphorylated STAT 1 levels and more normal mean skin thickness following JAK inhibitor (JAKi) treatment, according to Nordmann et al Within two days, the disease ceased to advance; within four days, reepithelialization was observed; after sixteen days, it was nearly complete (95%) and all patients were released after full recovery. On day 30 following JAKi treatment, all seven patients with TEN or SJS-TEN overlap syndrome were still alive and free of side effects. More prospective randomized studies are required to establish JAKi’s effectiveness against TEN, as it is a novel effective method for the condition that has not yet been proven in extensive clinical trials.⁶⁵

Supportive Treatment

Maintaining bodily fluid and electrolyte homeostasis, controlling body temperature, preventing and treating infections, providing respiratory and nutritional support, and providing adequate analgesia are all fundamental components of supportive care. Patients should ideally be treated in a specialized intensive care unit (ICU), such as a burn or skin ICU. Following treatment with early referral to burn hospitals, the mortality rate for TEN is less than 20%. Numerous studies that have been published in the literature in recent years support the decision to transfer TEN patients to burn centers. Because these specialized hospitals manage big area skin wounds appropriately and offer nutritional and intensive care assistance, early admission to burn centers appears to dramatically boost the survival of TEN patients.^24,66

Operative Treatment

Although the infection rate and mortality of TEN patients can be substantially decreased with timely and effective pharmacological therapy,⁶⁷ the infection induced by TEN patients through epidermal stripping still results in more difficulties and significantly affects the prognosis of patients. If patients receive associated treatments such biologic dressings, xenograft grafts, and intense supportive care, mortality can be successfully decreased. It has been discovered that biological, allograft, and xenograft dressings have antibacterial qualities that lessen discomfort, cut down on heat and evaporative loss, and encourage skin healing.⁶

According to a University of Washington Burn Center research conducted in Seattle, ten patients were hospitalized right away for surgery to close the wound and apply a xenograft, or pig skin, and all of them were, on average, fully reepithelialized in 18 days. According to studies, six children in the intensive care unit were managed by covering the detached skin area with a pig skin xenograft until re-epithelialization was finished. The average period from the pig xenograft’s installation to the skin’s full healing was 14 days.^68,69 Only two out of 29 participants (10%) died, according to a 2018 systematic analysis of the role of biologic skin substitutes in TEN and SJS that examined 29 xenograft usage cases with a mean TBSA participation of 73.87%.^70,71 According to some research, the 10 patients in the trial experienced a considerable decrease in biofilm pain, and the lesion healed fully in 14–21 days without leaving any noticeable scars or requiring skin grafting.⁷² In the case of large skin stripping patients, timely debridement surgery and the use of biological dressings to cover and protect the damaged wound can help to better relieve pain and reduce the associated complications caused by infection. This can help to minimize the source of skin infections, reduce fluid loss from the body, and lessen the pain associated with skin peeling.⁷³ The infection incidence of TEN patients is successfully decreased by this treatment plan, which also enhances prognosis and treatment quality. Research and study data regarding the surgical therapy of TEN are, nevertheless, scarce. We currently need to comprehend and investigate whether a new surgical technique will successfully lower the mortality rate, infection rate, and enhance the quality of patient prognosis.

Some progress has been achieved in treating TEN in the past, particularly the realization that the therapy used to treat burn patients can also be utilized to treat TEN patients, even if prevention and treatment of TEN remain pressing issues. Careful protection of the exposed dermis and degraded mucosal surfaces, nutritional support, close monitoring of systemic infection, antibiotic treatment, including TEN treatment, and fluid and electrolyte balance monitoring are some of these treatments. These all make it possible to further reduce TEN mortality rates.⁹

Summary and Outlook

The prognosis of patients’ lives is greatly impacted by TEN, a rare but dangerous disease with severe systemic symptoms, a greater death rate, and more complications. Thus, prompt, accurate, and early diagnosis is essential, as is effective care and treatment, all of which can enhance the prognosis of patients. There is currently a dearth of pertinent TEN data and analysis. Researching the associated risk factors and therapeutic approaches can increase the foundation for clinical care, lower the death rate among TEN patients, and enhance patient outcomes.