Allopurinol, a xanthine oxidase inhibitor, is widely used to treat conditions associated with hyperuricemia such as uric acid kidney stones, uric acid nephropathy during chemotherapy (tumor lysis syndrome), and gout. However, allopurinol is a frequent cause of adverse drug reactions, including severe cutaneous adverse reactions (SCARs). These reactions are particularly problematic given the rising prevalence of gout in the United States and other countries, which is driven by increased frequencies of conditions that promote hyperuricemia. These conditions include hypertension, obesity, metabolic syndrome, type 2 diabetes, and chronic kidney disease (CKD), in which the increase in the uric acid concentration is proportional to the decrease in glomerular filtration rate.

SCARs include drug hypersensitivity syndrome (DHS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). The spectrum of DHS, SJS, and TEN in response to allopurinol is frequently referred to as allopurinol hypersensitivity syndrome (AHS) and is estimated to occur in 1 of 1,000 allopurinol users in the United States. AHS is associated with marked morbidity and a mortality rate of 20% to 25%. Until recently, there was no way of predicting which patients were likely to develop AHS.

Human leukocyte antigen (HLA)-B alleles have been shown to be predictive of drug-induced adverse reactions. The Quest Diagnostics HLA-B*58:01 Typing assay determines the presence of the HLA-B*58:01 allele and thus identifies patients at increased risk of allopurinol-induced SCARs.

An early study of Han Chinese found the HLA-B*58:01 allele to be present in 100% of patients with allopurinol-induced SCARs, but in only 15% of allopurinol-tolerant controls.  Subsequent studies confirmed the association between HLA-B*58:01 and allopurinol-induced SCARs in Japanese, Korean, Thai, and European individuals. The odds of an adverse reaction were 29- to 580-fold greater for individuals with an HLA-B*58:01 allele than for those without, with odds being highest for Han Chinese and Thai populations. Similar to risk odds, HLA-B*58:01 allele frequencies vary by race or ethnicity; they are highest in Han Chinese, Thai, and Korean populations and lower in European and Japanese populations (see table).

Risk levels and allele frequencies are factored into guidelines for gout management and for allopurinol. The American College of Rheumatology guidelines recommend consideration of HLA-B*58:01 genotyping before allopurinol therapy in populations with a high HLA-B*58:01 allele frequency and at high risk for AHS (eg, all patients of Han Chinese or Thai descent and Koreans with stage 3 or worse CKD). The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines note that HLA-B*58:01 has a high negative predictive value, particularly in Asian patients; thus, testing for the allele could reduce the risk of SCARs. The CPIC guidelines also recommend against the use of allopurinol in HLA-B*58:01 carriers and recommend consideration of an alternative therapy in these patients.

Learning Objectives 

• Recognize new genetic testing can now predict the risk of severe cutaneous adverse reactions (SCARs) to allopurinol. 
• Learn about the spectrum of allopurinol hypersensitivity syndrome (AHS), including drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. AHS is estimated to occur in 1 of 1,000 allopurinol users in the United States. AHS is associated with marked morbidity and a mortality rate of 20% to 25%.
• Understand HLA-B*58:01 allele frequencies vary by race or ethnicity; they are highest in Han Chinese, Thai, and Korean populations and lower in European and Japanese populations. Studies confirm the association between HLA-B*58:01 and allopurinol-induced SCARs in Japanese, Korean, Thai, and European individuals. The odds of an adverse reaction were 29- to 580-fold greater for individuals with an HLA-B*58:01 allele than for those without.
• Learn about new guidelines for gout management and for allopurinol. The American College of Rheumatology and the Clinical Pharmacogenetics Implementation Consortium recommend HLA-B*58:01 genotyping before allopurinol therapy
• The Quest Diagnostics HLA-B*58:01 Typing assay determines the presence of the HLA-B*58:01 allele and thus identifies patients at increased risk of allopurinol-induced SCARs.