Should a patient of Japanese descent be tested for the HLA-B*5801 allele prior to starting allopurinol?

HLA-B*5801 Testing for Japanese Patients Before Allopurinol

Testing for HLA-B*5801 should be conditionally recommended for a man of Japanese descent prior to starting allopurinol, though the evidence is less robust than for other Southeast Asian populations.

Guideline Recommendations

The 2020 American College of Rheumatology guidelines specifically recommend HLA-B*5801 testing for patients of Southeast Asian descent (Han Chinese, Korean, Thai) and African American patients before initiating allopurinol 1. However, Japanese patients are notably not explicitly included in this high-priority testing group, despite being geographically and ethnically related to other East Asian populations 1.

Risk Assessment for Japanese Patients

Allele Prevalence

• The HLA-B*5801 allele prevalence is highest among Han Chinese, Korean, and Thai populations at 7.4% 1
• Japanese populations have a lower prevalence than other Southeast Asian groups, with rates closer to 1-6% 1
• This intermediate prevalence places Japanese patients at higher risk than European ancestry populations (0.7%) but lower than the specifically named Southeast Asian groups 1

Clinical Risk

• The HLA-B*5801 allele confers an odds ratio of 80-580 for allopurinol hypersensitivity syndrome (AHS) 1
• AHS carries a devastating 25% mortality rate and can manifest as Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, and severe cutaneous adverse reactions 1, 2
• All East Asian patients exposed to allopurinol who developed severe cutaneous reactions in documented case series were HLA-B*5801 positive, representing preventable cases 3

Clinical Decision Algorithm

For Japanese patients, consider the following approach:

1. Assess additional risk factors that increase hypersensitivity risk:

   • Chronic kidney disease stage 3 or worse (the ACR specifically recommends testing for Korean patients with CKD stage 3+) 1
   • Recent therapy initiation 1
   • Impaired renal function that elevates oxypurinol levels 1

2. If any high-risk features are present: Strongly consider HLA-B*5801 testing before allopurinol initiation 1, 4

3. If testing is positive: Allopurinol is contraindicated; use alternative urate-lowering therapy 1

4. If testing is negative or unavailable: Start allopurinol at low doses (≤100 mg daily, or 50 mg daily with CKD stage 4 or worse) and titrate slowly 1, 5

Cost-Effectiveness Considerations

Testing for HLA-B*5801 in Asian populations has been reported as cost-effective with incremental cost-effectiveness ratios <$109,000 per quality-adjusted life year 1. The test itself can be performed rapidly and inexpensively (as low as $3.80 USD per test) using validated screening methods 6.

Important Caveats

• The negative predictive value for HLA-B*5801 is not 100% in non-Southeast Asian populations, meaning a negative test does not completely eliminate risk 1
• Universal testing is conditionally recommended against in patients of other ethnic backgrounds, but Japanese patients occupy a gray zone not explicitly addressed 1
• Even without testing, proper dosing protocols (starting at ≤100 mg daily) have reduced acute gout attacks to <1% of patients 2

Practical Implementation

If you decide to test, several validated methods are available with 97.8-100% sensitivity, including flow cytometry and real-time PCR approaches 7, 6. A two-step strategy (flow cytometry screening followed by molecular confirmation) may reduce costs where both facilities are available 7.

The safest approach for Japanese patients is to offer HLA-B*5801 testing, particularly if CKD or other risk factors are present, while ensuring proper low-dose initiation and gradual titration regardless of testing status 1, 4, 2.