The Classification of SJS: A Type B Idiosyncratic Reaction
Stevens-Johnson Syndrome (SJS) is classified as a Type B, or idiosyncratic, adverse drug reaction (ADR). Unlike Type A reactions, which are predictable extensions of a drug's pharmacology and dose-dependent, idiosyncratic reactions are unpredictable and occur in a susceptible subgroup of the population. This unpredictability is why identifying the specific cause of SJS can be challenging and requires a high index of suspicion from healthcare providers.
Further classifying the underlying immunology, SJS is also specifically identified as a Type IV, subtype C, delayed hypersensitivity reaction. In contrast to immediate-type hypersensitivity reactions involving antibodies (e.g., IgE in anaphylaxis), Type IV reactions are cell-mediated, meaning they involve T-lymphocytes that attack the body's own cells. This cell-mediated response results in a delayed onset of symptoms, typically occurring several days to a few weeks after exposure to the triggering agent. The latency of this reaction can sometimes obscure the link between the medication and the onset of the condition, making a detailed drug history essential for diagnosis.
The Immunological Mechanism: A T-Cell Mediated Attack
The central pathology of SJS is a T-cell mediated immune response that results in widespread apoptosis, or programmed cell death, of epidermal keratinocytes. The process begins when a drug or one of its metabolites acts as a hapten, a small molecule that binds to and modifies a larger host protein. The body's antigen-presenting cells then display this altered protein-hapten complex to T-cells.
Alternatively, a drug might bind directly to certain human leukocyte antigen (HLA) proteins on the T-cell surface, a process known as the 'p-i' (pharmacological interaction with immune receptors) concept. This interaction inappropriately activates cytotoxic T-cells (CD8+) and natural killer (NK) cells. These activated immune cells then release cytotoxic molecules, such as granulysin, which trigger the extensive apoptosis of skin and mucosal epithelial cells. This cellular destruction leads to the painful blistering and shedding of the outer layers of the skin, a hallmark of SJS.
SJS and Toxic Epidermal Necrolysis (TEN): A Clinical Spectrum
SJS and Toxic Epidermal Necrolysis (TEN) are widely recognized as two ends of a single disease spectrum, differing primarily in the percentage of body surface area (BSA) affected. The underlying pathophysiology and triggers are generally the same, but TEN represents the more severe manifestation. A middle category, SJS/TEN overlap, is used for cases with intermediate severity.
| Feature | Stevens-Johnson Syndrome (SJS) | Toxic Epidermal Necrolysis (TEN) |
|---|---|---|
| Severity | Less severe form of the spectrum | Most severe form of the spectrum |
| Affected BSA | Less than 10% epidermal detachment | More than 30% epidermal detachment |
| SJS/TEN Overlap | N/A | Exists when 10-30% BSA is detached |
| Mortality Rate | Approximately 5% mortality rate | Can reach 30–40% mortality |
| Mucosal Involvement | Present, often severe | Also present and extensive |
| Systemic Symptoms | Often includes fever, malaise | More profound systemic symptoms and higher risk of complications |
Common Triggers and Associated Risk Factors
The most frequent cause of SJS in adults is medication, while infections are more common triggers in children. A thorough medical history is paramount to identify potential culprits, as symptoms can arise within days or weeks of starting a new medication.
Commonly Implicated Medications:
- Antibiotics: Especially sulfonamides (e.g., trimethoprim-sulfamethoxazole), but also penicillins, cephalosporins, and fluoroquinolones.
- Anticonvulsants: Lamotrigine, carbamazepine, phenytoin, and phenobarbital are frequently associated.
- Gout Medications: Allopurinol is a significant trigger, especially in certain Asian populations with the HLA-B*58:01 allele.
- Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Particularly the oxicam type.
Risk Factors:
- Genetic Predisposition: Specific genetic variations, particularly in the HLA-B gene, are strongly linked to SJS. For example, HLA-B*15:02 is associated with carbamazepine-induced SJS in individuals of Southeast Asian descent.
- HIV/AIDS: Individuals with HIV infection have a significantly higher incidence of SJS, up to 100 times greater than the general population.
- Certain Infections: Infections such as Mycoplasma pneumoniae and cytomegalovirus can be triggers, particularly in children.
Clinical Presentation and Diagnosis
SJS often begins with a prodromal phase lasting 1 to 3 days, characterized by flu-like symptoms such as fever, fatigue, and a sore throat. This is followed by the rapid development of a widespread, painful red or purple rash. Within days, this rash progresses to form blisters, and the top layer of skin begins to shed. Critically, there is also extensive involvement of mucous membranes, including the mouth, eyes, and genitals, leading to painful erosions.
Diagnosis is primarily clinical, based on the characteristic skin and mucosal findings, the patient's drug history, and the percentage of BSA affected. A skin biopsy can be performed to confirm the diagnosis, showing full-thickness epidermal necrosis with minimal dermal inflammation. The Nikolsky sign, where gentle pressure causes skin to shear off, is often positive.
Management and Prevention Strategies
Given the severity of SJS, immediate hospitalization in a specialized intensive care or burn unit is typically required for management.
Treatment Principles:
- Drug Withdrawal: The single most important step is to immediately discontinue the suspected offending medication and all non-essential drugs.
- Supportive Care: This involves maintaining fluid and nutritional balance (sometimes via feeding tube), meticulous wound and eye care, and pain management.
- Pharmacological Treatment: The use of systemic corticosteroids and other immunomodulatory agents is controversial and managed on a case-by-case basis.
Prevention:
- Genetic Screening: For certain high-risk drugs in specific populations, genetic testing for associated HLA alleles is recommended. For instance, the FDA advises screening individuals of Asian ancestry for HLA-B*15:02 before starting carbamazepine.
- Medication Avoidance: Individuals who have experienced medication-induced SJS must permanently avoid the causative drug and chemically similar drugs to prevent potentially fatal recurrence.
- Patient Awareness: Educating patients about their condition and necessary precautions is vital for safety.
Conclusion In summary, SJS is a rare but life-threatening type B, or idiosyncratic, adverse drug reaction that manifests as a severe Type IV delayed hypersensitivity response. Its core pathophysiology involves a T-cell mediated attack on the skin and mucous membranes, leading to widespread epidermal detachment. Recognizing SJS as part of a spectrum with TEN is key to understanding its severity, which is determined by the percentage of body surface area involved. Accurate diagnosis relies on a detailed patient history and clinical examination, while the most critical step in management is the immediate and permanent withdrawal of the causative drug. Preventative strategies, including pharmacogenomic screening in at-risk populations and vigilant patient education, offer the best hope for reducing the incidence and morbidity of this severe condition. For more information on SJS, visit the Mayo Clinic page on the topic: Stevens-Johnson syndrome.
