Clinical Pharmacogenetics Implementation Consortium Guidelines for Human Leukocyte Antigen-B Genotype and Allopurinol Dosing

Abstract

Allopurinol is the most commonly used drug for the treatment of hyperuricemia and gout. However, allopurinol is also one of the most common causes of severe cutaneous adverse reactions (SCARs), which include drug hypersensitivity syndrome, Stevens–Johnson syndrome, and toxic epidermal necrolysis. A variant allele of the human leukocyte antigen (HLA)-B, HLA-B*58:01, associates strongly with allopurinolinduced SCAR. We have summarized the evidence from the published literature and developed peer-reviewed guidelines for allopurinol use based on HLA-B genotype.

Clinical characteristics and treatment outcome of Stevens-Johnson syndrome and toxic epidermal necrolysis

“…The difference between these results could be explained by the common medications previously reported as having cutaneous adverse reactions now being avoided. With advancements in the identification of specific human leukocyte antigen (HLA) alleles that are associated with drug reactions, screening to identify patients at risk for drug reaction is becoming a part of standard clinical practice in certain academic institutions (18)(19)(20)(21). This could be one of the reasons why the incidence of drug reactions toward commonly known medications appears to have declined.…”

HLA-B*58:01is a risk factor for allopurinol-induced DRESS and Stevens-Johnson syndrome/toxic epidermal necrolysis in a Portuguese population

“…This discrepant strength of association may be related to the different prevalence of this HLA allele in the normal population, which is high in Han Chinese (10-15%) and low (1-2%) in Europeans. 1,26 Among patients with DRESS in this study, the percentage of HLA-B*58:01 carriers was much higher in female subjects Table 2 Comparative frequencies of HLA-B*58:01 in patients with severe cutaneous adverse drug reactions (CADR) to allopurinol in allopurinolexposed and -tolerant individuals and in the general population with calculation of odds ratio (OR) for the different types of CADR (81%) than in male subjects (38%). We found no previous published report on this sex difference, which may be just a spurious association.…”

“…Moreover, the high prevalence of HLA-B*58:01 in allopurinol-tolerant controls in populations with a high prevalence of this allele, might unnecessarily limit the use of this cheap drug, and replace it with other xanthine oxidase inhibitors (febuxostat) or other uric acid-lowering agents, which may be less efficacious, more expensive or with fewer long-term safety studies. 1,48,49 However, pregenotyping in populations with a high prevalence of HLA-B*58:01 may prevent a significant number of severe, even fatal cases. One may question the cost-effectiveness of its regular use in populations with a prevalence of HLA-B*58:01 below 2%, such as ours.…”

“…39 With the present universal recommendation to pretest for HLA-B*57:01, hypersensitivity from abacavir has almost completely disappeared and genotyping for HLA-B*15:02 in Han Chinese before carbamazepine therapy has significantly reduced SJS/TEN induced by this drug in Taiwan. 45 Genotyping before allopurinol is a matter of debate, 1,6,21,22,46,47 although new techniques are being developed to lower the cost and accelerate the procedures. 46,47 As the negative predictive value is well below 100%, particularly in Europeans, pretesting will not eliminate all cases.…”

“…Severe CADR (sCADR), sometimes fatal, occur in up to 0Á4%. 1,2 It is one of the most frequent causes of sCADR worldwide [3][4][5][6][7] and responsible for most cases of CADR requiring hospitalization in Portugal. 8 Allopurinol causes several patterns of CADR due to delayed hypersensitivity, namely maculopapular exanthema (MPE), DRESS (drug reaction with eosinophilia and systemic symptoms), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) 4 and, less frequently, fixed drug eruption (FDE) 9 or acute generalized exanthematous pustulosis (AGEP).…”