Impact of the HLA-B58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions

Abstract

Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01, we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio [OR] = 44.0; 95% confidence interval = 21.5-90.3; P = 2.6 × 10(-41)), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate < 30ml/minute/1.73 m(2)) should be cautious and avoid using allopurinol.

HLAs: Key regulators of T‐cell‐mediated drug hypersensitivity

“…Functional studies indicate that HLA‐B*58:01 restricted reactivity is stronger to the metabolite oxypurinol than the parent drug. This and non‐covalent interactions between HLA‐B*58:01 and oxypurinol are supported by the fact that allopurinol is rapidly metabolised to oxypurinol and patients with renal insufficiency are at higher risk of developing allopurinol SJS/TEN and DRESS and have a poorer prognosis . These later data are consistent with the dose dependency evidenced during the induction of allopurinol and oxypurinol specific T‐cell lines …”

Gout: An old disease in new perspective – A review

“…Risk factors include recent (<3 months) allopurinol initiation, use of allopurinol for asymptomatic hyperuricemia, female gender [156], a history of skin reaction to allopurinol, HLA∗B-5801 carriage [157], [158], high initial dose [159] and renal failure [160], [161].…”

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System

“…Among the culprit drugs associated with renal involvement, allopurinol is the most notorious one [26]. Allopurinol-induced SCAR is significantly associated with the human leukocyte antigen (HLA)-B*58:01 allele in Han Chinese patients with a gene dosage effect [27,28]. Allopurinol-induced SCAR is more likely to develop in patients with underlying renal impairment because of the prolonged clearance of an allopurinol metabolite, oxypurinol, observed in these patients [29,30].…”