What gene predisposes to hypersensitivity and Stevens-Johnson syndrome (SJS) with allopurinol?

HLA-B*58:01 Allele Predisposes to Allopurinol-Induced Hypersensitivity and Stevens-Johnson Syndrome

The HLA-B*58:01 allele is the primary genetic marker that strongly predisposes individuals to allopurinol-induced hypersensitivity reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). 1

Genetic Association and Risk

• HLA-B*58:01 is present in 100% of patients with allopurinol-induced severe cutaneous adverse reactions (SCAR) in Han Chinese populations, with odds ratios of 80-580:1 for developing hypersensitivity reactions 1, 2
• The association is particularly strong in Asian populations but also significant in European populations, where 55-61% of allopurinol-induced SJS/TEN patients carry the HLA-B*58:01 allele 3
• The prevalence of HLA-B*58:01 varies by ethnicity: 9-11% in Han Chinese, 1-6% in European ancestry populations, 4% in African Americans, and 11% in Africans 1

Mechanism of Hypersensitivity

• Oxypurinol, the active metabolite of allopurinol, preferentially binds to the peptide binding groove of HLA-B*58:01, forming a highly immunogenic drug-peptide-HLA complex that initiates the hypersensitivity reaction 1, 4
• This complex triggers a T-cell mediated immune response leading to the severe cutaneous and systemic manifestations 1
• Risk is further increased by impaired renal function, which elevates levels of allopurinol and oxypurinol 1

Clinical Implications and Recommendations

• The 2012 American College of Rheumatology Guidelines recommend preemptive HLA-B*58:01 genetic testing for:
  • Patients of Korean descent with CKD stage 3 or worse (allele frequency of 5%)
  • Persons of Han-Chinese or Thai descent regardless of kidney function 1
• The 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines state that allopurinol is contraindicated in persons of any ethnicity with a positive genetic test for HLA-B*58:01 1
• HLA-B*58:01 testing has a negative predictive value of 100% in Han Chinese populations, but slightly lower in non-Southeast Asian populations 1
• The positive predictive value is approximately 3%, with a number needed to test of 250 to prevent one case 1

Clinical Manifestations of Allopurinol Hypersensitivity

• Allopurinol-induced hypersensitivity is devastating with a 25% mortality rate 1, 4
• Common manifestations include:
  • Cutaneous: erythematous skin rash, SJS, TEN 1
  • Systemic: fever, eosinophilia (elevated leukocyte counts with 20% eosinophils) 1, 4
  • Hepatic: hepatitis, elevated transaminases 1
  • Renal: worsening kidney function 1, 4
  • DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) 1

Testing Methods

• Several methods exist for HLA-B*58:01 detection, including DNA sequencing and loop-mediated isothermal amplification (LAMP) 5, 6
• LAMP assay has been confirmed as simple, rapid, and specific for HLA-B*58:01 detection 6
• Testing should be considered prior to initiating allopurinol therapy, especially in high-risk populations 1, 5

Management of Patients with HLA-B*58:01

• Patients who test positive for HLA-B*58:01 should be prescribed alternative medications to allopurinol 1, 4
• For patients who have already experienced allopurinol hypersensitivity, immediate discontinuation of the drug and supportive care are essential 1, 4
• Systemic corticosteroids may be considered to manage inflammatory manifestations 4
• Future avoidance of allopurinol is mandatory in patients who have experienced hypersensitivity reactions 1, 4

Pitfalls and Caveats

• HLA-B*58:01 is necessary but not sufficient for developing allopurinol-induced SJS/TEN, suggesting other factors contribute to the reaction 3
• Recent initiation of therapy is a significant risk factor, with most reactions occurring within the first few weeks of treatment 1
• Starting with lower doses (50-100 mg daily) and gradual titration may reduce risk, especially in patients with renal impairment 4
• Concomitant use of thiazide diuretics may increase the risk of adverse reactions 4