An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing

Abstract

Purpose: This study was conducted to evaluate the usefulness of human leukocyte antigen (HLA) typing in preventing allopurinolinduced severe cutaneous adverse reactions (SCARs) through the application of an allopurinol tolerance induction protocol or prescription of other alternative medications in high-risk patients.Methods: HLA typing was performed in patients with chronic renal insufficiency who needed allopurinol. HLA-B*58:01-negative patients were prescribed the usual dose of allopurinol. For HLA-B*58:01-positive patients, administration of either allopurinol based on a 28-day tolerance induction protocol or alternative medications was initiated. Hypersensitivity reactions were surveyed for 90 days and compared with the result of a previous retrospective cohort study.

Allopurinol hypersensitivity: investigating the cause and minimizing the risk

“…4,14,27 As AHS mostly occurs within 6 months of starting allopurinol therapy, it is quite possible that an initial exposure to high antigen levels is the key factor in the development of drug-specific T cells. 27 In agreement with this possibility are the results of a study by Jung et al,47 which showed that an allo purinol 'tolerance induction protocol' in HLA-B*58:01-positive patients with chronic kidney impairment reduced the development of SCAR.…”

“…47 This 28-day allopurinol desensitiz ation protocol begins with very small doses of allopurinol to introduce the drug in patients at increased risk. 47 None of the patients with the HLA-B*58:01 allele and kidney impairment developed AHS, suggesting that such a protocol could be used with reasonable safety. However, it should be noted that the final dose in this study was low (103.45 ± 42.11 mg daily) and whether slow dose-titration can be used beyond the initial 90 days with a similar decreased risk of developing AHS needs to be explored in future studies.…”

“…45 However, HLA class II molecules, rather than HLA class I molecules, typi cally activate CD4 + T cells, which is consistent with the fact that the HLA-B*58:01 allele does not seem to be associated with the development of MPE. [46][47][48] On the other hand, drug-specific cytotoxic CD8 + T cells are likely to be responsible for SJS/TEN, with granu lysin being the key mediator of the widespread epidermal necrosis. 40,49 Both CD4 + and CD8 + T cells are implicated in DRESS, along with reactivation of herpes viruses such as human herpesvirus 6, Epstein-Barr virus and cyto megalovirus.…”

HLA and Delayed Drug-Induced Hypersensitivity

“…Moreover, renal insufficiency is associated with a poor prognosis, correlating with higher mortality and prolonged cutaneous reactions [97]. This evidence contests the dogma that type B adverse reactions are totally unpredictable and dose independent, thus opening the possibility for their prevention by desensitization techniques [94,98]. In fact, no SCAR episodes were observed after Jung et al [98] treated a sample of patients with a high risk of allopurinol-induced SCAR (HLA-B*58:01+ carriers with chronic kidney disease) to a tolerance induction protocol consisting of a gradual increase in allopurinol dose [98].…”

“…This evidence contests the dogma that type B adverse reactions are totally unpredictable and dose independent, thus opening the possibility for their prevention by desensitization techniques [94,98]. In fact, no SCAR episodes were observed after Jung et al [98] treated a sample of patients with a high risk of allopurinol-induced SCAR (HLA-B*58:01+ carriers with chronic kidney disease) to a tolerance induction protocol consisting of a gradual increase in allopurinol dose [98]. As previously mentioned, viral infections also appear to increase the risk of allopurinol-induced DDAR [37,38].…”