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Allopurinol is widely used for hyperuricemia-related diseases such as gout, Lesch-Nyhan syndrome, and recurrent urate kidney stones. However, allopurinol is one of the most common causes of severe cutaneous adverse reactions (SCAR), a spectrum of reactions that includes drug hypersensitivity syndrome, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which may include a constellation of features such as eosinophilia, vasculitis, rash, and major end-organ disease. There is a reported mortality rate of 20% to 25% for SCAR.
Studies in Han Chinese residing in Taiwan showed that the HLA-B*58:01 allele was present in 100% of the patients with allopurinol-induced skin reactions, but in only 15% of allopurinol-tolerant controls. Data obtained from recombinant mapping further concluded that HLA-B*58:01 itself is the major susceptibility gene for allopurinol-induced skin reactions in the Han Chinese population. In the Thai population, 100% of patients with allopurinol-induced skin reactions carried the allele, but only 13% of allopurinol-tolerant individuals tested positive for the HLA-B*58:01 allele. A similar but more modest 80% of Korean cases compared to 12% of healthy controls and 56% of Japanese cases compared to 0.61% of healthy controls were positive for the HLA-B*58:01 allele. Two studies of Europeans have been reported. In the first study, 55% of European cases compared to 1.5% of controls tested positive for the allele and, in the second study, 100% of cases compared to a population frequency of 1.5% were positive for the HLA-B*58:01 allele. A meta-analysis that considered all published studies as of the date of the analysis gave the odds ratios for allopurinol-induced severe skin reactions in HLA-B*58:01 carriers as 73 and 165 compared to healthy controls and allopurinol-tolerant controls, respectively. The frequency of the HLA-B*58:01 allele is widely distributed among other populations: (eg, 2%-4% in Africans, 3%-15% in Asian Indians). Further studies are needed to determine if individuals from these populations with this allele are at similar risk for allopurinol hypersensitivity reaction.
Guidelines have been developed by the Clinical Pharmacogenomics Implementation Consortium that recommends that HLA-B*58:01 genotyping be performed and that allopurinol should not be prescribed to patients who test positive for the allele. Also, guidelines developed by the 2012 American College of Rheumatology for Management of Gout recommend that HLA-B*58:01 testing should be considered in select patient subpopulations at an elevated risk for AHS. Those of Korean descent, especially those with stage 3 or higher chronic kidney disease, or of Han Chinese or Thai extraction irrespective of renal function should be tested. However, given the literature as reviewed above, consideration should be given to testing all patients who will be given allopurinol.
Identifying individuals with an increased risk of severe cutaneous adverse reactions to allopurinol
Positivity for HLA-B*58:01 confers risk for hypersensitivity to allopurinol
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.
Rare, unreported HLA-B alleles may occur and may interfere with this assay resulting in a false-positive or false-negative call. This assay also detects closely related, but rare, alleles including HLA-B*57:05, *58:04, *58:05, *58:09, *58:10, *58:11, *58:12, *58:13, *58:15, *58:17, *58:19, *58:21, *58:22, *58:23, *58:24, and *58:28. There are, as yet, no data indicating whether these subtypes are associated with hypersensitivity.
1. Chung WH, Hung SI, Chen YT: Human leukocyte antigens and drug hypersensitivity. Curr Opin Allergy Clin Immunol 2007;7:317-323
2. Khanna D, Fitzgerald J, Khanna P, et al: 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res 2012;64:1431-1446
3. Hershfield MS, Callaghan JT, Tassaneeyakul W, et al: Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther 2013 Feb;93(2):153-158