A table summarizing all the key HLA genes associated with Steven-Johnson Syndrome (SJS), including their population risk and associated medications.
HLA Gene | Associated Drug(s) | Population Risk | Clinical Implications |
HLA-B*1502 | Carbamazepine | High risk in Southeast Asians, especially Han Chinese, Thai, Filipino populations | Strong association with carbamazepine-induced SJS; pre-treatment screening recommended in at-risk populations. |
HLA-A*3101 | Carbamazepine | More common in Europeans, Japanese, and Han Chinese | Broader association with SJS and other cutaneous reactions; screening may be considered, especially in European populations. |
HLA-B*5801 | Allopurinol | High risk in Han Chinese, Korean, and Thai populations | Strong association with allopurinol-induced SJS/TEN; pre-treatment screening recommended in at-risk populations. |
Steven-Johnson Syndrome (SJS) is a severe, immune-mediated hypersensitivity reaction that affects the skin and mucous membranes. Despite its rarity, SJS has garnered significant attention in clinical practice due to its high morbidity and mortality rates. Understanding the role of HLA (human leukocyte antigen) genes in predisposing individuals to SJS is crucial for both preventive and therapeutic strategies, especially as genetic screening becomes more accessible in clinical settings.
What is Steven-Johnson Syndrome?
SJS is most commonly triggered by certain medications, though infections and idiopathic causes are also recognized. It is a part of a spectrum of severe cutaneous adverse reactions (SCARs), which also includes toxic epidermal necrolysis (TEN). SJS and TEN are differentiated primarily by the extent of skin detachment: in SJS, it involves less than 10% of the body surface area, whereas in TEN, it involves more than 30%. The hallmark of SJS is widespread epidermal necrosis, often beginning with a prodrome of fever and malaise, followed by painful, blistering lesions that affect the skin and at least two mucosal surfaces (oral, ocular, and genital).
Pathophysiology of SJS: The Role of HLA
The pathophysiology of SJS is rooted in an immune-mediated reaction that involves cytotoxic T cells. These T cells target keratinocytes, leading to massive apoptosis of skin and mucosal cells, mediated largely by granulysin. The initiation of this immune cascade is often drug-induced and critically influenced by specific HLA alleles that present the drug (or its metabolite) as a foreign antigen, triggering an immune response.
The genetic predisposition to SJS has been most clearly demonstrated through associations with HLA class I alleles, particularly in patients taking medications like carbamazepine, allopurinol, and phenytoin. Below, we discuss the most significant HLA associations linked to SJS.
Key HLA Alleles Associated with SJS
HLA-B*1502:
Population risk: Predominantly observed in Southeast Asians, especially in individuals of Chinese, Thai, and Filipino descent.
Associated drug: Carbamazepine. This association is so strong that the FDA and European Medicines Agency recommend screening for HLA-B*1502 in at-risk populations before initiating carbamazepine.
Pathophysiology: In HLA-B*1502 carriers, carbamazepine is presented to cytotoxic T cells in a way that leads to T-cell activation and subsequent epidermal damage.
Clinical implications: Screening patients for HLA-B*1502 before starting carbamazepine significantly reduces the risk of SJS in susceptible populations. Alternative anticonvulsants should be considered if a patient is positive for this allele.
HLA-A*3101:
Population risk: More broadly distributed, found in individuals of European, Japanese, and Han Chinese descent.
Associated drug: Carbamazepine. Although the association is less strong compared to HLA-B1502, HLA-A3101 still poses a considerable risk, especially for milder forms of hypersensitivity reactions, including maculopapular eruptions, in addition to SJS.
Clinical implications: While not as widely recommended as HLA-B1502 testing, screening for HLA-A3101 can be useful in European populations where this allele is more common.
HLA-B*5801:
Population risk: Common in Han Chinese populations, with notable prevalence in other East Asian groups.
Associated drug: Allopurinol, used widely for gout and hyperuricemia, is the most common trigger of allopurinol-induced SJS and TEN.
Pathophysiology: Allopurinol or its metabolite oxypurinol binds to HLA-B*5801, which triggers cytotoxic T-cell activation and subsequent keratinocyte apoptosis.
Clinical implications: Screening for HLA-B5801 before prescribing allopurinol is recommended in high-risk populations. Alternatives such as febuxostat should be considered in HLA-B5801 carriers.
Mechanisms of HLA-Mediated Drug Reactions
The HLA molecules present processed peptides on the surface of cells to T cells, allowing the immune system to distinguish between self and non-self. However, in individuals carrying specific HLA alleles, drugs or their metabolites are misrecognized as harmful antigens. This inappropriate presentation results in the activation of CD8+ cytotoxic T cells and the release of perforins and granzymes, leading to widespread apoptosis of epithelial cells. Granulysin, a cytolytic protein, plays a central role in this massive keratinocyte death, making it a marker of disease severity.
Why Genetic Screening Matters
Given the strong genetic predisposition linked to specific HLA alleles, screening high-risk patients can significantly reduce the incidence of SJS. For example, HLA-B*1502 testing in Southeast Asian populations is now a standard of care before prescribing carbamazepine. Similarly, HLA-B*5801 screening is critical before initiating allopurinol in East Asian populations.
Such preemptive measures are particularly important because of the high mortality rate of SJS and TEN, which can exceed 30% in severe cases. Early recognition, drug cessation, and supportive care in an intensive care or burn unit are essential for improving patient outcomes.
Clinical Application: Who Should Be Screened?
Carbamazepine users: Anyone of Asian ancestry (Southeast Asia, Southern China, India) should be screened for HLA-B*1502 before starting treatment.
Allopurinol users: Patients of Han Chinese, Korean, or Thai descent should be screened for HLA-B*5801.
Broader populations: For European or Japanese populations, consideration of HLA-A*3101 screening may be warranted before initiating carbamazepine.
Conclusion
Steven-Johnson Syndrome is a life-threatening condition, with certain HLA alleles serving as strong predictors of risk in drug-induced cases. As pharmacogenetics continues to advance, the clinical utility of HLA screening becomes increasingly important in preventing adverse drug reactions like SJS. By integrating genetic testing into routine clinical practice, particularly in high-risk populations, we can reduce the incidence of this devastating syndrome and improve patient safety.
For clinicians, staying informed about the genetic predispositions and recognizing when to apply genetic screening is critical for preventing SJS and optimizing drug safety. Ultimately, this represents a significant step toward personalized medicine, tailoring drug prescriptions to the genetic makeup of individual patients.
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