Why is checking for HLA (Human Leukocyte Antigen)-B*5801 important before starting allopurinol?

HLA-B*5801 Testing Before Allopurinol Therapy: Preventing Life-Threatening Hypersensitivity Reactions

Testing for HLA-B*5801 before starting allopurinol therapy is essential for preventing potentially fatal hypersensitivity reactions, particularly in high-risk ethnic populations including Southeast Asian descent (Han Chinese, Korean, Thai) and African American patients.

Understanding Allopurinol Hypersensitivity Syndrome (AHS)

Allopurinol hypersensitivity syndrome is a devastating adverse effect with significant mortality and morbidity:

• AHS has an estimated mortality rate of 25% and occurs in approximately 1:1000 patients in the USA 1
• Clinical manifestations include Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and severe cutaneous adverse reactions (SCAR) 1, 2
• Common features include erythematous skin rash, eosinophilia, hepatitis, and reduced kidney function 1

HLA-B*5801 and Risk Association

The HLA-B*5801 allele is strongly associated with allopurinol hypersensitivity:

• Patients carrying the HLA-B*5801 allele have dramatically increased risk of developing AHS, with odds ratios estimated between 80 to 580:1 1
• The mechanism involves oxypurinol (allopurinol's active metabolite) preferentially binding to the peptide binding groove of HLA-B*5801, forming a highly immunogenic drug-peptide-HLA complex that triggers hypersensitivity 1, 2
• In a Thai population study, 100% of allopurinol-induced SJS/TEN patients carried HLA-B*5801 with an odds ratio of 348.3 3

Ethnic Variations in HLA-B*5801 Prevalence

The prevalence of HLA-B*5801 varies significantly across ethnic groups:

• Highest prevalence in Han Chinese, Korean, and Thai populations (6-8%) 1
• Lower but significant prevalence in African Americans (3.8%) 1
• Much lower prevalence in white and Hispanic populations (0.7% each) 1
• These differences correlate with observed risk variations, with Asian and African American patients having a 3-fold increased risk of AHS compared to white patients 1

Current Guidelines for HLA-B*5801 Testing

The American College of Rheumatology provides specific recommendations:

• 2020 guidelines conditionally recommend HLA-B*5801 testing before starting allopurinol for patients of Southeast Asian descent (Han Chinese, Korean, Thai) and African American patients 1
• Testing is conditionally recommended against in patients of other ethnic backgrounds 1
• Testing among Asian and African American patients is cost-effective with incremental cost-effectiveness ratios <$109,000 per quality-adjusted life year 1

Clinical Impact of HLA-B*5801 Testing

Implementation of HLA-B*5801 testing has demonstrated significant clinical benefits:

• A 2015 study showed complete prevention of SCARs in HLA-B*5801-positive patients when using either a tolerance induction protocol or alternative medications 4
• Compared to historical controls, there was a significant reduction in SCARs (0% vs. 18%, p=0.002) 4
• HLA-B*5801 testing demonstrated 100% sensitivity and 87% specificity for predicting allopurinol-induced SJS/TEN in a Thai population 3

Recommendations for Clinical Practice

When considering allopurinol therapy:

1. Test for HLA-B*5801 in high-risk populations:

   • Southeast Asian descent (Han Chinese, Korean, Thai) regardless of renal function 1
   • Korean patients with CKD stage 3 or worse (allele frequency ~12%) 1
   • African American patients 1

2. If HLA-B*5801 positive:

   • Prescribe an alternative to allopurinol 1, 2
   • Consider febuxostat or uricosuric agents as alternatives 1

3. If HLA-B*5801 negative or testing not indicated:

   • Start allopurinol at low dose (≤100 mg daily, lower in CKD) 1
   • Gradually increase dose to reach target serum urate levels 2

Common Pitfalls to Avoid

• Failing to test high-risk populations: Not testing Southeast Asian or African American patients puts them at unnecessary risk 1
• Starting with high doses: Even in HLA-B*5801 negative patients, starting with doses >100 mg daily increases risk 1
• Overlooking renal function: Impaired renal function elevates levels of allopurinol and oxypurinol, increasing hypersensitivity risk 1
• Ignoring concurrent medications: Thiazide diuretics can increase the risk of AHS 2

By implementing HLA-B*5801 testing in appropriate populations before initiating allopurinol therapy, clinicians can significantly reduce the risk of potentially fatal hypersensitivity reactions while still providing effective treatment for hyperuricemia and gout.