Etiology of Stevens-Johnson Syndrome
Stevens-Johnson syndrome is primarily caused by medications, with sulfonamide antibiotics, anticonvulsants (particularly carbamazepine, lamotrigine, phenytoin, phenobarbital), allopurinol, nevirapine, oxicam NSAIDs, and sulfasalazine being the most notorious culprits, though infections—particularly Mycoplasma pneumoniae in children—account for a significant proportion of cases. 1, 2
Primary Etiologic Categories
Medication-Induced (Most Common in Adults)
The British Association of Dermatologists identifies the following high-risk medications that most commonly cause SJS/TEN 1, 2:
- Allopurinol (particularly common in adults, rare in children) 1, 3
- Anticonvulsants: Carbamazepine, lamotrigine, phenytoin, phenobarbital 1, 2, 4
- Sulfonamide antibiotics (sulfamethoxazole and other sulfonamides) 1, 2, 5
- Sulfasalazine 1, 2
- Nevirapine 1, 2
- Oxicam NSAIDs (meloxicam, piroxicam) 1, 2
The latency period between drug initiation and SJS onset is typically 5-28 days, unless there is prior exposure to the same drug, which may shorten the latency. 1
Pediatric-Specific Etiology
In children, both infections and drugs are important triggers, with infections accounting for up to 50% of cases—a stark contrast to adults where medications predominate. 1, 6
The most commonly implicated medications in pediatric populations are 1, 7:
- Antibiotics (42% of drug-related cases in one Thai series) 7
- Anticonvulsants (35% of drug-related cases) 7, 3
- NSAIDs and paracetamol (though these may be confounders as they are often given for prodromal symptoms) 1, 2
Notably, allopurinol, oxicams, and nevirapine are rarely identified as causative agents in children due to differences in prescribing patterns compared to adults. 3
Infectious Etiology
When a causative drug cannot be identified, Mycoplasma pneumoniae infection should be strongly considered, particularly in children where it accounts for up to 50% of infection-related cases. 1, 2, 6
Other infectious triggers include 6:
The British Journal of Dermatology guidelines specifically recommend considering mycoplasma infection when no drug culprit can be identified 1.
Pathophysiologic Mechanism
SJS is an immunologically mediated delayed-type hypersensitivity reaction where drug-specific CD8+ T-cells and natural killer cells induce keratinocyte apoptosis through release of cytotoxic mediators including Fas ligand, perforin/granzyme, tumor necrosis factor, and granulysin. 5, 8
Histologically, this manifests as multiple apoptotic keratinocytes throughout the full thickness of the epidermis with subepidermal split formation and a perivascular lymphocytic infiltrate 1.
Genetic Predisposition
Certain HLA genotypes significantly increase susceptibility to drug-induced SJS in specific ethnic populations. 4
Key genetic associations include 4:
- HLA-B*15:02 in Chinese and Southeast Asian populations increases risk with lamotrigine and carbamazepine
- HLA-B*31:01 in Japanese populations increases risk with the same anticonvulsants
- HLA-B*44:03 in Korean populations similarly increases risk
Critical Clinical Pitfalls
Paracetamol and ibuprofen are frequently falsely implicated due to the "protopathic effect"—they are often started for prodromal fever and symptoms that actually represent early SJS, not the cause of it. 1, 2 However, one series reported higher complication risk in children who received ibuprofen, so caution is warranted 1.
Any suspected medication must be withdrawn immediately as this decreases mortality risk—this is the single most important intervention. 1, 2, 3 A complete drug history covering the 2 months prior to symptom onset should be obtained from multiple sources including the patient, relatives, GP, and pharmacist 1.