Personalized Medicine for HLA-associated Drug-hypersensitivity Reactions

Mandvi Bharadwaj; Patricia Illing; Lyudmila Kostenko

Disclosures

Personalized Medicine. 2010;7(5):495-516. 

In This Article

Allopurinol Hypersensitivity & HLA-B*5801

Allopurinol is a urate-lowering drug that has been the cornerstone in the treatment of hyperuricaemia and gout for decades. It acts as a suicide substrate for xanthine oxidase, the enzyme responsible for conversion of xanthine to uric acid. Enzyme inhibition is mediated by enzyme catalyzed oxidation to oxypurinol, which coordinates irreversibly with the reduced molybdenum center of the enzyme to prevent enzyme oxidation and recovery.[51] In most patients, allopurinol is well tolerated; however, approximately 2% of treated patients develop a skin rash.[52]

In 2005, a Taiwanese group published data indicating a strong association between allopurinol–HSS and SJS/TEN and HLA-B*5801 in the Han Chinese population. A total of 100% of their hypersensitive cohort possessed HLA-B*5801, whilst the allele was present in only 15% of the tolerant group and 20% of the population controls.[16] This association was later observed in both Japanese and Thai populations,[17,18] and to a lesser extent in a European population.[53] The presence of HLA-B*5801 in the tolerant group once again indicates the involvement of other factors in hypersensitivity.

To date, no studies have looked at the role of T cells or HLA-B*5801 in the development of the disease; however, the delayed onset of hypersensitivity after initial drug administration[16] and the involvement of CD8+ T cells in SJS/TEN development once again favor the hypothesis that HLA-B*5801 is a risk factor in these hypersensitivities owing to mechanistic involvement in T-cell activation. Despite this knowledge gap, the development of a rapid screen for HLA-B*5801 has already occurred with a view to its implementation for prevention of allopurinol-induced hypersensitivities.[54] No data has been published with regards to the success of such screening.

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