Dataset Information

Racial/ethnic variation and risk factors for allopurinol-associated severe cutaneous adverse reactions: a cohort study.

ABSTRACT: OBJECTIVES:To examine associations of race/ethnicity and purported risk factors with hospitalised allopurinol-associated severe cutaneous adverse reactions (AASCARs). METHODS:We used US Medicaid data to identify incident allopurinol users between 1999 and 2012. We examined the risk of hospitalised AASCARs according to race/ethnicity and purported key risk factors and calculated relative risks (RR). RESULTS:Among 400?401 allopurinol initiators, we documented 203 hospitalised AASCAR cases (1 in 1972 initiators). The average AASCAR hospitalisation was 9.6 days and 43 individuals (21%) died. The multivariable-adjusted RRs for AASCARs among blacks, Asians and Native Hawaiians/Pacific Islanders compared with whites or Hispanics were 3.00 (95% CI 2.18 to 4.14), 3.03 (95% CI 1.72 to 5.34) and 6.68 (95% CI 4.37 to 10.22), respectively. Female sex, older age (?60 years), chronic kidney disease and initial allopurinol dose (>100?mg/day) were independently associated with a 2.5-fold, 1.7-fold, 2.3-fold and 1.9-fold higher risk of AASCAR, respectively. In our combined demographic analysis, older women (?60 years) of a high-risk race/ethnicity (blacks, Asians or Native Hawaiians/Pacific Islanders) had over a 12-fold higher risk of hospitalised AASCARs than younger men of a low-risk race/ethnicity (whites or Hispanics) (multivariable-adjusted RR, 12.25; 95%?CI 6.46 to 23.25). CONCLUSIONS:This racially diverse (yet mostly white) cohort study indicates that the risk of hospitalised AASCAR is rare overall, although blacks, Asians and Native Hawaiians/Pacific-Islanders have a substantially higher risk of hospitalised AASCARs, particularly among older women. These data also support the practice of initiating allopurinol at a low dose (eg, ?100?mg/day).

SUBMITTER: Keller SF

PROVIDER: S-EPMC6045437 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Racial/ethnic variation and risk factors for allopurinol-associated severe cutaneous adverse reactions: a cohort study.

Keller Sarah F SF Lu Na N Blumenthal Kimberly G KG Rai Sharan K SK Yokose Chio C Choi Jee Woong J JWJ Kim Seoyoung C SC Zhang Yuqing Y Choi Hyon K HK

Annals of the rheumatic diseases 20180413 8

<h4>Objectives</h4>To examine associations of race/ethnicity and purported risk factors with hospitalised allopurinol-associated severe cutaneous adverse reactions (AASCARs).<h4>Methods</h4>We used US Medicaid data to identify incident allopurinol users between 1999 and 2012. We examined the risk of hospitalised AASCARs according to race/ethnicity and purported key risk factors and calculated relative risks (RR).<h4>Results</h4>Among 400 401 allopurinol initiators, we documented 203 hospitalised ...[more]

PMID: 29653927

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Project description:ObjectiveTo evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol treatment.DesignNational prospective cohort study.Setting15 medical centres in different regions of Taiwan, from July 2009 to August 2014.Participants2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants' peripheral blood was used to assess the presence of HLA-B*58:01.Main outcome measuresIncidence of allopurinol induced SCARs with and without screening.ResultsParticipants who tested positive for HLA-B*58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test).ConclusionsProspective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence of allopurinol induced SCARs in Taiwanese medical centres.

Project description:Allopurinol-related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA-B*58:01, the allele frequency (AF) of which is largely different among East Asians. However, evidence of population differences in SCAR development and relevance of genetic and/or other risk factors in the real-world remain unelucidated. This study aimed to evaluate population differences in allopurinol-related SCAR incidence related to genetic and/or other risk factors among East Asians in the real-world. A population-based cohort study was conducted using claims databases from Taiwan, Korea, and Japan. New users of allopurinol (311,846; 868,221; and 18,052 in Taiwan, Korea, and Japan, respectively) were followed up to 1 year. As control drugs, phenytoin and carbamazepine were used. The crude incidence rate ratios (IRRs) of SCARs for allopurinol against phenytoin or carbamazepine were the highest in Taiwan (IRR, 0.62 and 1.22; 95% confidence interval [CI], 0.54-0.72 and 1.01-1.47, respectively), followed by Korea (IRR, 0.34 and 0.82; 95% CI, 0.29-0.40 and 0.77-0.87), and the lowest in Japan (IRR, 0.04 and 0.16; 95% CI, 0.02-0.08 and 0.09-0.29). This order was accordant with that of AF ratios (AFRs) reported of HLA-B*58:01 against alleles responsible for phenytoin- or carbamazepine-related SCARs. The IRRs were higher in patients with chronic kidney disease, females, and elderly. This study demonstrated population differences in the risk of allopurinol-related SCAR development among East Asians based on genetic and other common risk factors. This finding will help to promote appropriate risk management for allopurinol-related SCARs based on ethnic origins. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC? Allopurinol-related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA-B*58:01, the allele frequency of which is largely different among East Asians. However, there is no direct real-world evidence of population differences in SCAR development and the influence of genetic factors and/or other risk factors. WHAT QUESTION DID THIS STUDY ADDRESS? Do population differences in development of allopurinol-related SCARs, depending on genetic factors and/or other risk factors, exist among three East Asians in the real-world? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The current analysis, based on comparisons of relative risks of SCAR incidence, provides real-world evidence of population differences in allopurinol-related SCAR development risk among East Asians, which was consistent with differences in reported HLA-B*58:01 frequencies, as well as identifying chronic kidney disease, female gender, and old age as common risk factors. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study helps to promote appropriate risk management strategies for allopurinol-related SCARs in the real-world considering risk factors based on the patients' ethnicity. Our approach is useful for evaluating population differences in the real-world.

Project description:PURPOSE:Nonsteroidal anti-inflammatory drugs (NSAIDs) are common cause of severe cutaneous adverse reactions (SCARs). The present study aimed to investigate the characteristics of SCARs induced by NSAIDs in the Korean SCAR registry. METHODS:A retrospective survey of NSAID-induced SCARs recorded between 2010 and 2015 at 27 university hospitals in Korea was conducted. Clinical phenotypes of SCARs were classified into Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS-TEN overlap syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS). Causative NSAIDs were classified into 7 groups according to their chemical properties: acetaminophen, and propionic, acetic, salicylic, fenamic and enolic acids. RESULTS:A total of 170 SCARs, consisting of 85 SJS, 32 TEN, 17 SJS-TEN overlap syndrome and 36 DRESS reactions, were induced by NSAIDs: propionic acids (n=68), acetaminophen (n=38), acetic acids (n=23), salicylic acids (n=16), coxibs (n=8), fenamic acids (n=7), enolic acids (n=5) and unclassified (n=5). Acetic acids (22%) and coxibs (14%) accounted for higher portions of DRESS than other SCARs. The phenotypes of SCARs induced by both propionic and salicylic acids were similar (SJS, TEN and DRESS, in order). Acetaminophen was primarily associated with SJS (27%) and was less involved in TEN (10%). DRESS occurred more readily among subjects experiencing coxib-induced SCARs than other NSAID-induced SCARs (62.5% vs. 19.7%, P = 0.013). The mean time to symptom onset was longer in DRESS than in SJS or TEN (19.1 ± 4.1 vs. 6.8 ±1.5 vs. 12.1 ± 3.8 days). SCARs caused by propionic salicylic acids showed longer latency, whereas acetaminophen- and acetic acid-induced SCARs appeared within shorter intervals. CONCLUSIONS:The present study indicates that the phenotypes of SCARs may differ according to the chemical classifications of NSAIDs. To establish the mechanisms and incidences of NSAID-induced SCARs, further prospective studies are needed.

Project description:Background: Allopurinol-induced severe cutaneous adverse reactions (SCARs), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), are life-threatening autoimmune reactions. Evidence is growing that epigenetic variation, particularly DNA methylation, is associated with autoimmune diseases. However, the potential role of aberrant DNA methylation in allopurinol-SCARs is largely unknown. Objective: To address the knowledge gap between allopurinol-SCARs and DNA methylation, we studied the DNA methylation profiles in peripheral blood cells from allopurinol-SCARs and allopurinol-tolerant subjects. Methods: A genome-scale DNA methylation profiling was conducted using the Illumina Infinium HumanMethylation450 (HM450) platform on 15 patients with allopurinol-SCARs (3 TEN, 2 SJS/TEN overlap and 10 SJS) and 20 age- and gender-matched allopurinol-tolerant controls at disease onset. Pyrosequencing was used to validate the candidate CpG (cytosine-guanine dinucleotide) sites in an independent cohort of 40 allopurinol-SCARs and 48 allopurinol-tolerants. Results: After bioinformatics analysis of methylation data obtained from HM450 BeadChip, we identified 41 differentially methylated CpG loci (P < 0.05) annotated to 26 genes showing altered DNA methylation between allopurinol-SCARs and allopurinol-tolerants. Among these genes, significant hypomethylation of PSORS1C1 (cg24926791) was further validated in a larger sample cohort, showing significant difference between DRESS and controls (P = 0.00127), ST (SJS and TEN) and controls (P = 3.75 × 10-13), and SCARs and controls (P = 5.93 × 10-15). Conclusions: Our data identified differentially methylated genes between allopurinol-SCARs and allopurinol-tolerant controls and showed that PSORS1C1 hypomethylation was associated with allopurinol-SCARs (OR = 30.22, 95%CI = 4.73-192.96) during disease onset, suggesting that aberrant DNA methylation may be a mechanism of allopurinol-SCARs. Limitations: Firstly, the data come from whole blood samples known to possess epigenetic heterogeneity, i. e., blood samples comprise a heterogeneous cell population with varying proportions of distinct cell-types with different DNA methylation patterns. Consequently, the interpretation of DNA methylation results should be performed with great caution due to the heterogeneous nature of the sample. Secondly, whether the identified disease-associated changes of epigenome precede disease onset, or result from the disease progression, needs further investigation. Comparing the methylation status before patients develop allopurinol-SCARs and after may help examine methylation levels from disease onset to disease progression.

Dataset Information

Racial/ethnic variation and risk factors for allopurinol-associated severe cutaneous adverse reactions: a cohort study.

Publications

Racial/ethnic variation and risk factors for allopurinol-associated severe cutaneous adverse reactions: a cohort study.

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