1. Epidemiology & Demographics

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe mucocutaneous adverse reactions. Their incidence is low, but mortality is directly correlated with the extent of epidermal detachment, underscoring the need for rapid diagnosis and specialized care.

1.1 Incidence & Mortality

Globally, SJS/TEN affects between 1 and 9 individuals per million each year. Mortality rises sharply as the affected body surface area (BSA) increases.

1.2 Geographic & Genetic Factors

Incidence patterns reveal strong pharmacogenetic associations, particularly in certain ethnic groups. For instance, carbamazepine-induced SJS/TEN is more common in Southeast Asian populations due to the higher prevalence of the HLA-B15:02 allele. Similarly, allopurinol-related reactions are more frequent in Han Chinese and Korean populations carrying the HLA-B58:01 allele. This has led to successful preventative screening programs in some regions; pre-prescription HLA-B*15:02 screening in Taiwan reduced the incidence of carbamazepine-induced SJS/TEN by over 90%.

2. Drug Triggers & Latency Periods

Medications are the primary cause of SJS/TEN, implicated in over 70% of cases. The reaction is typically a delayed, type IVc hypersensitivity response, with a characteristic latency period between drug initiation and symptom onset.

2.1 High-Risk Medications

A few drug classes account for the majority of cases. The risk is highest during the first 8 weeks of therapy.

2.2 Latency and Causality Assessment

The typical onset of symptoms is 4 to 28 days after starting a new high-risk medication. A shorter latency of less than 7 days may suggest prior sensitization or re-challenge. In cases of polypharmacy, determining the culprit drug can be challenging. The ALDEN (Algorithm of Drug Causality for Epidermal Necrolysis) is a validated tool used to retrospectively assess the probability of each suspected drug being the cause.

3. Immunologic Pathophysiology

SJS/TEN is fundamentally a T-cell-mediated process where the body’s immune system mistakenly attacks its own skin and mucosal cells, leading to widespread cell death (apoptosis) and detachment.

3.1 Key Mediators

• Type IVc Hypersensitivity: This classification denotes a T-cell-mediated reaction where cytotoxic CD8+ T-cells are the primary drivers of tissue damage.
• Granulysin: This is considered the principal cytotoxic protein responsible for keratinocyte death in SJS/TEN. Its concentration in blister fluid directly correlates with disease severity.
• Other Molecules: Perforin/granzyme B pathways and the engagement of the Fas receptor on keratinocytes by Fas Ligand (FasL) on T-cells also contribute significantly to the apoptotic cascade. Interleukin-15 (IL-15), released by stressed keratinocytes, further amplifies the cytotoxic immune response.

4. Genetic & Host Susceptibility

A patient’s genetic makeup, specifically their Human Leukocyte Antigen (HLA) type, is the single most important risk factor for developing SJS/TEN in response to certain drugs. These associations are so strong that they form the basis for preventative screening.

5. Impact of Chronic Comorbidities

Certain underlying chronic diseases, particularly those involving immune dysregulation, dramatically increase the risk of SJS/TEN and are associated with poorer outcomes.

5.1 HIV/AIDS

Patients with HIV infection have a risk of developing SJS/TEN that is up to 1,000 times higher than that of the general population. The exact reasons are multifactorial but are thought to involve chronic immune activation, altered drug metabolism pathways, and a higher burden of coinfections that may act as co-triggers.

6. Social Determinants of Health

Socioeconomic factors, access to care, and health literacy can significantly impact the timely diagnosis and management of SJS/TEN, thereby influencing patient outcomes.

6.1 Access and System-Level Barriers

In many settings, delays in seeking medical care are common due to cost, geographic distance to facilities, or lack of transportation. Furthermore, the absence of established referral pathways to specialized burn centers or ICUs can lead to prolonged exposure to the culprit drug and a delay in initiating critical supportive care, worsening morbidity and mortality.

6.2 Health Literacy and Cultural Factors

Low health literacy can prevent patients from recognizing early warning signs (e.g., fever, mucosal pain, spreading rash) and linking them to a new medication. This can delay the crucial first step: cessation of the offending drug. In some cultures, initial reliance on traditional remedies can further complicate the identification of the trigger and delay presentation to a medical facility.

7. Clinical Implications & Research Directions

Early and accurate risk stratification is crucial for predicting prognosis and guiding the level of care. Ongoing research is focused on identifying early biomarkers and novel therapeutic targets to halt disease progression.

7.1 Risk Stratification Scores

Validated scoring systems help predict mortality at the time of admission. SCORTEN is the most widely used, while ABCD-10 offers an alternative with enhanced focus on renal risk factors.

7.2 Biomarkers and Future Therapies

The future of SJS/TEN management lies in earlier diagnosis and targeted intervention. Blister-fluid granulysin and serum IL-15 are promising biomarkers that correlate with severity and may one day serve as rapid diagnostic tools. Therapeutically, research is exploring agents that can modify the immune response, such as RIP kinase inhibitors (to block necroptosis) and other T-cell modulating therapies, to stop the destructive cascade before significant tissue damage occurs.