Stevens-Johnson syndrome (SJS) is a rare but dangerous adverse drug reaction (ADR) that falls into two pharmacological classification categories: Type B (idiosyncratic) and Type IVc (delayed hypersensitivity). As a Type B reaction, it is unpredictable and not related to the drug's known pharmacology. As a Type IVc reaction, it is an immunological response involving cytotoxic T-cells and is not dose-dependent. This powerful and often fatal immune-mediated attack is what makes SJS so severe and requires prompt recognition and treatment.
The Immunological Mechanism: A Type IVc Hypersensitivity
The severity of SJS stems from its core mechanism: a robust T-cell-mediated cytotoxic reaction. The body's immune system, specifically cytotoxic T lymphocytes (CD8+ T-cells) and natural killer (NK) cells, is mistakenly activated to attack and destroy the body's own skin cells (keratinocytes) and mucosal epithelial cells.
This cellular destruction is facilitated by several potent cytotoxic mediators released by the activated T-cells and NK cells:
- Granulysin: A protein found in cytotoxic granules, Granulysin is a primary driver of keratinocyte apoptosis (programmed cell death). Its concentration in blister fluid has been shown to correlate with the disease's severity.
- Perforin and Granzyme B: These molecules work together in a process called granule exocytosis. Perforin creates pores in the target cell's membrane, allowing Granzyme B to enter and trigger a cascade of intracellular caspases, leading to cell death.
- Fas-Fas ligand (FasL) Pathway: The interaction between the Fas receptor on keratinocytes and the Fas ligand on activated T-cells and NK cells can also induce apoptosis, although the role of granulysin is now considered more significant.
The initiation of this T-cell assault is often linked to genetic predispositions, particularly specific human leukocyte antigen (HLA) alleles, combined with drug exposure. The drug or its metabolite may bind to an HLA protein on an antigen-presenting cell, triggering the T-cell response. An example is the strong association between the HLA-B*15:02 allele and carbamazepine-induced SJS in certain Asian populations.
Common Triggers: Medications and Beyond
While sometimes the cause is unknown, medication exposure is the most frequent trigger for SJS, especially in adults. The reaction typically occurs within 4 to 28 days of starting the medication, though it can happen sooner upon re-exposure.
Common drug classes and specific agents implicated in SJS/TEN include:
- Anticonvulsants: Carbamazepine, lamotrigine, phenytoin, and phenobarbital are high-risk triggers.
- Antibacterial Sulfonamides: Trimethoprim-sulfamethoxazole is a well-known culprit.
- Anti-gout medications: Allopurinol is a major cause, especially at higher doses.
- Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Certain oxicam-type NSAIDs, such as piroxicam and meloxicam, carry a higher risk.
- Antiretrovirals: Nevirapine, used in HIV treatment, is associated with an increased risk.
Infections are another significant trigger, particularly in children and adolescents, with Mycoplasma pneumoniae and herpes simplex virus being among the most common infectious causes. In immunocompromised patients, such as those with HIV, the risk of drug-induced SJS is substantially higher.
Clinical Manifestations and the SJS/TEN Spectrum
The presentation of SJS typically begins with a non-specific prodrome lasting several days, including fever, malaise, headache, and a sore throat, often mimicking a viral illness. These symptoms are followed by the rapid development of a painful, widespread skin rash involving red or purple macules and blisters. The distinguishing feature is the extensive involvement of at least two mucosal surfaces, including the mouth, eyes, genitals, and airways, which is almost universal in SJS.
SJS is part of a disease continuum with Toxic Epidermal Necrolysis (TEN), differentiated by the extent of epidermal detachment.
SJS vs. TEN: A Comparative View
| Feature | Stevens-Johnson Syndrome (SJS) | Toxic Epidermal Necrolysis (TEN) |
|---|---|---|
| Epidermal Detachment | Less than 10% of body surface area (BSA) | Greater than 30% of BSA |
| Overlapping SJS/TEN | 10-30% BSA detachment | Treated similarly to TEN due to severity |
| Severity | Less severe end of the spectrum | Most severe end of the spectrum |
| Mortality Rate | Around 5-10% | 30-40% or higher |
Diagnosis and Management
Early and accurate diagnosis is critical for a positive outcome. Diagnosis is typically based on clinical presentation, including a detailed medication history. A skin biopsy is often performed to confirm the diagnosis by revealing full-thickness epidermal necrosis and to rule out other dermatological conditions.
Initial treatment is focused on immediate intervention and supportive care, often in an Intensive Care Unit (ICU) or specialized burn unit. The most important step is the immediate cessation of all non-essential medications, especially the suspected causative agent, as early withdrawal improves prognosis.
Supportive care includes:
- Fluid and electrolyte management to combat dehydration from extensive skin loss.
- Aggressive wound care using non-adherent dressings, similar to the treatment for severe burns.
- Nutritional support via a nasogastric tube to promote healing.
- Pain management using systemic and topical medications.
- Ophthalmology consultation for specialized eye care, as ocular complications are common and can lead to blindness.
The use of immunomodulatory agents like systemic corticosteroids, intravenous immunoglobulin (IVIG), and cyclosporine remains controversial, with some studies showing mixed results or improved outcomes with early administration.
The Importance of Prevention
Prevention is paramount, especially for individuals with known risk factors. Key strategies include:
- Patient Education: Anyone who has had SJS must be informed of the culprit drug and warned to avoid it and chemically related drugs for life. Wearing a medical alert bracelet can be a vital safeguard.
- Genetic Screening: For certain high-risk drug-population pairs, genetic testing can identify predisposed individuals before treatment begins. The U.S. FDA recommends screening for the HLA-B15:02 allele in people of Asian ancestry before starting carbamazepine. Screening for HLA-B58:01 is also recommended for allopurinol in at-risk populations.
- Careful Medication Use: Prescribers should use caution when starting high-risk drugs, especially at higher initial doses or when combining certain agents, and be vigilant for early signs.
Conclusion
In summary, Stevens-Johnson syndrome is a severe Type IVc hypersensitivity reaction classified as a Type B, or idiosyncratic, adverse drug reaction. Its danger lies in the powerful, T-cell mediated autoimmune attack on the body's skin and mucosal surfaces, resulting in widespread epidermal necrosis. Triggered primarily by medications and, less commonly, infections, SJS and its more severe counterpart, TEN, represent a dermatological emergency requiring immediate drug withdrawal and intensive supportive care. Understanding the immunological basis of this ADR is key to early diagnosis, effective management, and ultimately, prevention through careful prescribing practices and genetic screening in at-risk populations. For more in-depth information, you can refer to a recent review on the topic.
