When should HLA (Human Leukocyte Antigen) B27 testing be considered before initiating allopurinol therapy?

HLA-B*5801 Testing Before Allopurinol

HLA-B*5801 testing should be performed before initiating allopurinol in patients of Southeast Asian descent (Han Chinese, Korean, Thai) and African American patients, but is not recommended for routine screening in other populations. 1

Population-Specific Recommendations

High-Risk Populations Requiring Testing

• Southeast Asian patients (Han Chinese, Korean, Thai): Testing is conditionally recommended regardless of renal function due to HLA-B*5801 allele frequency of 6-12% and hazard ratios in the hundreds for allopurinol hypersensitivity syndrome (AHS) 1

• African American patients: Testing is conditionally recommended due to 3.8% allele frequency and 3-fold increased risk of AHS compared to white patients 1

• Korean patients with stage 3 or worse CKD: Particularly high-risk subgroup with ~12% allele frequency warranting testing 1

Populations Where Testing is NOT Recommended

• White/Caucasian patients: Universal testing is conditionally recommended against due to low allele frequency (~0.7-2%) and substantially lower hazard ratios 1

• Hispanic patients: Testing not recommended given low allele frequency of 0.7% 1

Rationale for Risk Stratification

The HLA-B*5801 allele is the strongest genetic risk factor for AHS, which carries a 20-25% mortality rate and includes Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and systemic disease with eosinophilia, vasculitis, and major end-organ involvement 1, 2. Testing was found cost-effective (incremental cost-effectiveness ratios <$109,000 per quality-adjusted life years) specifically in Asian and African American populations 1.

In HLA-B*5801 positive patients from high-risk populations, prescribe an alternative urate-lowering therapy such as febuxostat rather than allopurinol. 1, 3

European Perspective Differs

The 2016 EULAR guidelines do not recommend systematic HLA-B*5801 screening even in high-risk populations, leaving it to physician discretion, citing insufficient data for cost-effective screening in European populations with low allele frequency 1. However, this represents a more conservative stance compared to the 2020 ACR guideline which provides clear population-specific recommendations 1.

Testing Methodology

• Use rapid PCR-based testing, which is widely available and requires follow-up sequencing in only ~10% of inconclusive results 1
• Testing only needs to be performed once in a patient's lifetime 4

Critical Timing Consideration

The highest risk of severe allopurinol hypersensitivity occurs in the first few months of therapy, with approximately 90% of AHS cases developing within 60 days of initiating allopurinol 1, 5. Therefore, testing must be completed before the first dose of allopurinol is administered in high-risk populations. 1

Alternative Management if HLA-B*5801 Positive

• First choice: Switch to febuxostat as alternative xanthine oxidase inhibitor 3
• Second option: Allopurinol desensitization protocols may be considered if no other oral urate-lowering therapy options are available 1, 3