Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Epidemiology, Risk Factors, and Drug Triggers: A Narrative Review

Fig. 1 [11]

Epidemiology:

Global incidence and prevalence:

A retrospective cohort study in Hong Kong found that the annual incidence of SJS/TEN was 5.07 cases per million [12]. The annual incidence of SJS and TEN is estimated to be between two and seven per one million per year, with SJS outnumbering TEN three to one [13], while the annual incidence of SJS and TEN in the general population is known to be 1-6 and 0.4-1.2 per million people, respectively, according to (Yang et al., 2016) [4]. Despite modest variations across research and populations, the incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis is continuously low globally, with only a few instances per million people per year. The greater prevalence of SJS compared to TEN is a repeating observation, but regional data, including those from Hong Kong, are within the worldwide reported range, indicating the credibility and generalizability of these epidemiological estimates. A higher proportion of cases were observed among older adults, particularly those aged 60-80 years, indicating that this age group may be more vulnerable to drug-induced Stevens-Johnson syndrome and Toxic Epidermal Necrolysis [14], though causality cannot be determined definitively. However, in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis, rising age has been demonstrated to independently predict poorer clinical outcomes, such as higher mortality, increased incidence of urinary tract infections, and acute renal injury. This finding is consistent with previous research, highlighting age as a key prognostic factor in SJS/TEN [15]. Although the population-level mortality of epidermal necrolysis is relatively low (about 0.9 cases per million inhabitants), there is a significant increase in mortality with advancing age, particularly among individuals aged ≥65 years, highlighting age as a key prognostic factor influencing survival outcomes [16]. Because the frequency is modest, long-term consequences are frequently noted, with ocular sequelae being the most common, followed by urethral sequelae [4].

Regional variations, with emphasis on India:

Following a retrospective review of 22 samples, 13 cases of SJS and 9 cases of TEN were reported. This study identifies antiepileptic medicines, particularly carbamazepine and phenytoin, as the leading causes of Stevens-Johnson syndrome and toxic epidermal necrolysis, followed by antibiotics such as ofloxacin. The disease primarily affected young to middle-aged adults, with most patients recovering well; however, the frequency of sequelae and sepsis-related death highlights the importance of early detection and rapid therapy of high-risk patients [17]. In 15 cases, multiple medicines were involved, while only one drug was responsible in 5. Antibiotics (40.7%) were identified as the most common cause, followed by NSAIDs (25.9%) and anticonvulsants (7.4%) [18]. This observation may be due to antibiotic usage patterns and accessibility, rather than an intrinsic greater risk profile as compared to other drug groups. Mortality rates in foreign studies range from 15.4 to 48%, while in Indian studies they range from 8.10 to 28.20% [5]. The lower reported mortality in some Indian series compared to Western cohorts may be due to case mix differences, referral bias, and challenges in capturing post-discharge deaths.

Mortality rates and trends:

The mortality rates for the SJS group, SJS-TEN overlap syndrome group, and TEN group were 5.4%, 14.4%, and 15.3%, respectively. Increasing age, chronic kidney disease, pneumonia, sepsis, and malignant neoplasms were all substantially linked with an increased risk of death [19]. SJS and TEN show a definite severity-dependent rise in mortality, with much higher rates in TEN than in SJS. Notably, mortality remains high even after the acute phase, as demonstrated by increased 6-week and 1-year mortality rates. However, pediatric patients appear to have a reduced mortality rate, indicating that disease behavior or resilience may change among age groups [20]. Pneumonia, life-threatening bacterial infections (sepsis), shock, multiple organ failure, and death are all serious consequences. Stevens-Johnson syndrome kills about 10% of patients, whereas toxic epidermal necrolysis kills up to 50% of people. Survivors of Stevens-Johnson syndrome and Toxic Epidermal Necrolysis typically endure long-term multisystem complications affecting the skin, mucosa and eyes. These long-term consequences, which range from pigmentary and nail alterations to functional impairments like vision disturbance and genitourinary dysfunction, underline the disease's chronic burden and the need for long-term, multidisciplinary care [21]. Observed mortality exceeded SCORTEN projections in SJS (16.9% vs 14.1%), but was lower than predicted in SJS/TEN overlap (22.2% vs 28.5%) and TEN (28.2% vs 36.9%), indicating differential calibration across severity levels [12].

Burden of disease:

As previously stated, the long-term burden of the disease has a substantial impact on quality of life, prognosis, and mortality rates. This refers to long-term hospitalization and ICU burn unit care. SJS/TEN survivors had an increased risk of incident cardiovascular disease events and mortality, which lasted 4 to 7 years after the original SJS/TEN. Older survivors and those admitted to the intensive care unit with SJS/TEN diagnosis had considerably greater rates of cardiovascular death (Chiu & Chiu, 2025) [6]. Management necessitates a multidisciplinary approach centered on supportive care and infection control, with new evidence supporting immunomodulatory medications such as cyclosporine and combination intravenous immunoglobulin and corticosteroids [2]. Stevens-Johnson syndrome and TEN place a significant strain on the Hong Kong hospital system due to their extended length of stay and high demand for critical care. Furthermore, due to screening issues and the need of multimodal interventions [12,22], it is a challenging condition to manage, not just financially but also emotionally and intellectually. This demonstrates that it is difficult to handle in a resource-constrained environment. Pharmacovigilance, rational prescribing, and preventative pharmacogenomic methods are crucial to address the disproportionate burden of drug-related cases, which are often preventable.

Risk factors:

Patient related factors- age, gender, comorbidities, HIV

According to a Korean incidence study, the incidence of SJS/TEN is lowest in the 20-29 age group and highest in the 70-year-old group [4]. The highest risk of mortality was determined to be over 40 years old [19]. Chronic kidney disease, pneumonia, sepsis, and race/ethnicity are all independent risk factors [5, 19]. HIV is a major risk factor for SJD/TEN, albeit many of them are caused by drugs. However, other sources claim that HIV increases the chance of the disorder by 100 times. Some causes include drugs such as nevirapine and trimethoprim-sulfamethoxazole, immunological dysregulation, and concurrent infections [13]. In HIV-infected individuals, TEN lesions show a decrease in skin-directed CD4+ cells and an increase in the ratio of CD8+ to CD4+ cells. This may increase the risk of drug reactions due to the loss of skin-protective CD4+CD25+ regulatory T cells [23]. In research conducted at SFGH, 50% of the patients tested positive for HIV, with TMP-SMX, atovaquone, clindamycin, and fluconazole identified as the causal medicines [3]. The incidence risk of SJS/TEN is 3:2 greater in women than in males, and the risk may increase in autoimmune/HIV patients [24]. As a result, pharmaceutical use is a more significant risk factor for HIV infection.

Genetic predisposition- HLA associations

The HLA-B*1502 allele significantly predicts carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis. Due to potential cross-reactivity, prescribing oxcarbazepine for HLA-B*1502+ patients are not recommended [9]. HLA-B*1502 is strongly associated with carbamazepine-induced SJS/TEN in the Han-Chinese, Thai, and Malaysian populations. HLA-B*1502 screening is recommended for patients requiring carbamazepine therapy [25]. There was also a substantial association between HLA-B*5801 and allopurinol-induced SJS/TEN. Therefore, HLA-B*5801 allele screening may be considered in patients who will be treated with allopurinol [26]. Another study conducted on the Japanese population found a substantial link between HLA-A*02:06 and acetaminophen-induced severe mucosal SJS/TEN [27]. Another study found a link between HLA-B*44:03 and SJS/TEN, and the medication trigger was cold medicine [28]. This genotype is also related with the development of SJS/TEN as a result of TMP-SMX, lamotrigine, acetaminophen, and trichloroethylene [29]. This establishes a framework for preventing such medication reactions based on population, ethnicity, and genetic risk. Other variables may include clinical considerations such as polypharmacy; in this instance, it may be difficult to pinpoint the exact drug trigger, and there may be a multidrug eruption.

Drug triggers:

SJS/TEN is caused by a complicated immunologic response to a related drug antigen and/or its metabolite, resulting in severe morbidity and mortality. Keratinocyte death is a result of complex immunological processes. Drug-induced SJS/TEN has been demonstrated to be highly HLA class I restricted, which has aided our knowledge of processes and has the potential to influence prevention and diagnosis [30]. Approximately six antiepileptic medicines (AEDs) have been identified as pharmacological triggers for SJS/TEN: lamotrigine, carbamazepine, phenytoin, zonisamide, rufinamide, and clorazepate [31].

SJS/TEN can be caused by a variety of medicines, although AEDs are the most prevalent, with lamotrigine, carbamazepine, and phenytoin being the most common [32]. HLAB*15:02 has been shown in Chinese and Southeast Asian individuals to increase sensitivity to lamotrigine and carbamazepine-induced SJS. Furthermore, patients of Japanese descent with HLAB*31:01 and Koreans with HLA-B*44:03 are at a higher risk of developing SJS after receiving the same two medications [32]. Because of the high link between HLA phenotypes and SJS, the FDA has issued a black box warning requiring screening for HLAB*15:02 before to prescribing these AEDs [32, 33, 34]. The combination of lamotrigine and valproic acid raises the risk of the condition [32]. An unusual case was reported in which a 7-year-old kid had SJS after taking clobazam, lamotrigine, and valproic acid [35]. As previously noted, cross reactions may occur, such as carbamazepine and oxcarbazepine [9]. The proportion of antibiotics linked to SJS/TEN globally was 28%. Sulphonamides were related with 32% of antibiotic-associated SJS/TEN cases, followed by penicillin (22%), cephalosporins (11%), fluoroquinolones (4%), and macrolides (2%), according to research [36]. HLA-B*44:03 is related with SJS/TEN induced by TMP-SMX [29]. Several HLA alleles have been linked to severe cutaneous adverse responses caused by beta-lactam antibiotics, with HLA-B50:01 having the highest overall risk and HLA-B46:02 showing a substantial association with Stevens-Johnson syndrome / Toxic Epidermal Necrolysis. However, after correcting for multiple comparisons, these relationships lost statistical significance, indicating that the findings should be regarded with caution and validated in bigger research. Notably, HLA-A*02:07 may be protective against beta-lactam-induced responses [37]. HLA-A11:01 has been discovered as a substantial genetic risk factor for sulphonamide-induced severe cutaneous adverse reactions, with a strong link to both Stevens-Johnson syndrome / Toxic Epidermal Necrolysis and Drug Reaction with Eosinophilia and Systemic Symptoms. After correcting for multiple comparisons, this connection remained statistically significant and was constant among distinct SCAR phenotypes, indicating that HLA-A11:01 may play an essential role in vulnerability to sulphonamide-induced responses. However, the small sample size necessitates cautious interpretation and further validation in larger cohorts [38]. A Thai population showed a substantial correlation between allopurinol-induced SJS/TEN and the HLA-B*5801 allele. The findings indicate that HLA-B*5801 is a useful genetic marker for screening Thai people who may be at risk of allopurinol-induced life-threatening SJS and TEN [39]. Testing for the pharmacogenetic HLA-B*58:01 allele prior to allopurinol therapy could considerably lower the incidence of SJS/TEN and related mortality, making it a cost-effective intervention [40]. Furthermore, a substantial link was discovered between HLA-A*33:03 and HLA-C*03:02 alleles and allopurinol-induced SJS or TEN, particularly in an Asian population [41]. To prevent the reaction, an alternate medicine, such as febuxostat or probenecid, may be administered.

NSAIDs may cause Stevens-Johnson syndrome and Toxic Epidermal Necrolysis through a variety of interconnected mechanisms, including retinoid toxicity-induced hepatic injury, mitochondrial dysfunction leading to hepatocyte death, immune-mediated keratinocyte apoptosis via Fas-FasL signaling and cytotoxic mediators, and sulfonamide-induced structural hypersensitivity. These mechanisms cause extensive keratinocyte death and epidermal detachment [42]. A review of 1,868 cases of Stevens-Johnson syndrome linked to NSAID use revealed variation in drug-specific risk and outcomes. Among the agents tested, ibuprofen showed the strongest connection, with the highest reporting odds ratio (ROR = 7.06), proportional reporting ratio (PRR = 6.98), and empirical Bayes geometric mean (EBGM = 6.78). Despite this, ibuprofen-associated SJS had the lowest death rate (6.87%) but the highest hospitalization rate (79.27%). In contrast, diclofenac was associated with the highest mortality (25.00%), indicating more severe effects. Celecoxib had the longest time to onset (317.56 days), indicating a delayed presentation. These findings indicate significant variability in risk and clinical outcomes across NSAIDs linked to SJS [42]. Nevirapine is a well-known cause of severe cutaneous adverse responses, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, with a reasonably high prevalence in adult populations. The observed link between higher baseline CD4+ counts and pregnancy supports an immune-mediated mechanism, maybe triggered by increased immunological reactivity at the time of medication administration. Genetic vulnerability adds to risk, highlighting the importance of host factors in determining unfavorable outcomes. In contrast, the reduced prevalence recorded in pediatric groups, particularly the rarity of cases in neonates despite widespread prophylaxis, could be due to differences in immunological maturity, medication metabolism, or underrecognition. The reporting of newborn instances, while relatively restricted, demonstrates that risk exists and emphasizes the importance of vigilance. Importantly, early detection and timely termination of nevirapine remain significant predictors of positive outcomes, underlining the importance of rigorous risk assessment and monitoring throughout medication commencement [43]. The found connection between CYP2B6 c.983T>C and nevirapine-induced Stevens-Johnson syndrome / Toxic Epidermal Necrolysis implies that altered drug metabolism plays a role in illness vulnerability. While the absence of significance in the replication cohort may reflect insufficient statistical power, the consistency of effect direction and significance in pooled analysis reinforces the case for this link. The lack of connection with other hypersensitivity characteristics suggests probable specificity for severe cutaneous reactions. Together, these findings point to a complex etiology including both pharmacokinetic and immunogenetic factors [44]. A total of 3,471 cases of Stevens-Johnson syndrome and Toxic Epidermal Necrolysis were found among 159 anticancer medication combinations, with 31 agents exhibiting substantial signs. Targeted treatments and chemotherapy made similar contributions, followed by immunotherapies. The median onset time was 17 days, showing an early incidence following therapy initiation. Older age (>65 years), female gender, and certain medicines have been identified as independent risk factors [45].

CONCLUSION:

Stevens-Johnson syndrome and Toxic Epidermal Necrolysis are still among the most severe and devastating adverse medication reactions seen in clinical practice. Although uncommon, these disorders are linked with high mortality, substantial epidermal degradation, multisystem involvement, and major long-term sequelae that impact survivors well beyond the acute period of sickness. Advances in understanding SJS/TEN immunopathogenesis, particularly the significance of cytotoxic immune responses, granulysin-mediated keratinocyte death, and HLA-associated genetic vulnerability, have significantly increased understanding of disease causes and preventative measures. The substantial link between specific medications and pharmacogenetic risk alleles emphasizes the growing importance of precision medicine and population-based screening approaches in minimizing preventable cases. Early identification of high-risk patients, rapid withdrawal of the offending medication, and timely beginning of supportive multidisciplinary treatment remain critical components of management. Emerging immunomodulatory treatments, such as cyclosporine, and combination regimens incorporating corticosteroids and intravenous immunoglobulin, may have therapeutic benefits; however, more high-quality evidence is needed to create standardized treatment guidelines. Beyond the acute clinical manifestations, SJS/TEN have a significant and sometimes underappreciated impact on patients, caregivers, healthcare systems, and society. Survivors typically report chronic visual issues, pigmentary changes, mucosal damage, psychological stress, social stigma, a lower quality of life, and persistent fear of future medicine use. The significant economic burden associated with prolonged hospitalization, intensive care utilization, rehabilitation, and long-term follow-up highlights the importance of preventive initiatives and better healthcare planning. Strengthening pharmacovigilance systems, encouraging rational prescribing practices, including pharmacogenomic screening in vulnerable populations, and raising physician knowledge are all critical steps toward reducing the incidence and severity of SJS/TEN. Future research should not only concentrate on therapeutic breakthroughs, but also on survivorship care, psychological rehabilitation, and fair access to specialized treatment, especially in resource-constrained regions. A comprehensive and patient-centered strategy is thus essential for decreasing the overall burden of SJS/TEN and improving long-term outcomes for affected patients.

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