HLA-B*58:01 is an Incomplete Predictor of Allopurinol-Induced Severe Cutaneous Adverse Reactions

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Campbell , Matthew S. Krantz , Alexis Yu , Elizabeth J. Phillips , the SJS Survivor Study doi: https://doi.org/10.1101/2025.05.23.25328236 Chelsea N. Campbell 1 Department of Pathology, Microbiology, and Immunology, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee 2 Center for Drug Safety and Immunology, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee MS Find this author on Google Scholar Find this author on PubMed Search for this author on this site Matthew S. Krantz 2 Center for Drug Safety and Immunology, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alexis Yu 2 Center for Drug Safety and Immunology, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee MPH Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elizabeth J. Phillips 1 Department of Pathology, Microbiology, and Immunology, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee 2 Center for Drug Safety and Immunology, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: elizabeth.j.phillips{at}vumc.org Abstract Full Text Info/History Metrics Data/Code Preview PDF ABSTRACT Importance Carriage of HLA-B*58:01 has been shown to have a strong association with the development of allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and drug reaction and eosinophilia and systemic symptoms (DRESS) in many populations globally; however, there is a critical need to determine if this is generalizable to varying populations including those in the United States (US). Objective To perform HLA class I and II association studies in a cohort of US patients diagnosed with allopurinol-induced SJS/TEN or DRESS compared to allopurinol tolerant and population controls. Design, Setting, and Participants We enrolled consenting individuals who had specialist adjudicated allopurinol-induced SJS/TEN or DRESS (collectively allopurinol-SCAR). HLA carriage in these cases was compared to allopurinol tolerant and population controls identified through Vanderbilt University Medical Center (VUMC) BioVU, a biobank which includes 94,489 individuals with imputed human leukocyte antigen (HLA) class I and II typing from genotyping array data. Main Outcomes and Measures We performed HLA class I and II conditional logistic regression case-control analyses between allopurinol-SCAR cases and both population controls and allopurinol tolerant controls matched on age, sex, and self-identified race. We reported odds ratio (OR) and 95% confidence interval (CI) with Bonferroni corrected P ( Pc ) <.05. Results The conditional logistic regression analyses included allopurinol-SCAR cases (n=16) and 10:1 matched allopurinol tolerant controls (n=160). We found two HLA class I alleles independently associated with increased risk of allopurinol-induced SCAR: HLA-B*58:01 (OR 28 [95% CI, 8.6 – 100.6]) and HLA-A*34:02 (OR 20.6 [95% CI, 3.3 – 131.1]). We did not identify any HLA class II alleles meeting the Pc level of significance. Conclusions and Relevance We found HLA-B*58:01 to be strongly associated with allopurinol-induced SCAR, generalizing findings from previous studies. Additionally, we found HLA-A*34:02 to be a second independent genetic risk factor for allopurinol-SCAR. These findings underscore the need to conduct specific population-based studies that both reproduce known and uncover novel HLA associations in order to reduce harm through contributions to screening, risk stratification, and diagnosis. Question Is the association between HLA-B*58:01 and allopurinol-SCAR generalizable to admixed populations in the US or are additional HLA associations involved? Findings In this HLA association study with 16 patients of primarily self-identified Black race of adjudicated allopurinol-induced SJS/TEN or DRESS, we demonstrate a strong association with the established risk allele, HLA-B*58:01, and, for the first time, identified HLA-A*34:02 as an additional independent risk factor. Meaning HLA-B*58:01 is absent in more than one-third of our US cohort of allopurinol-SCAR cases suggesting that more comprehensive screening and diagnostic approaches are necessary to prevent additional cases in genetically heterogenous populations. INTRODUCTION Severe cutaneous adverse reactions (SCAR) are T-cell mediated reactions to medications resulting in significant morbidity and mortality globally. SCAR phenotypes include Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). One of the most common drugs implicated in SCAR is the uric acid lowering-agent, allopurinol. While carriage of HLA-B*58:01 has been reported to contribute to 100% of allopurinol-induced SCAR (allopurinol-SCAR) cases in Han Chinese populations 1 , this is not true in Northern and Southern European populations where only 55-64% of cases carried HLA-B*58:01 2 , 3 . Chronic kidney disease (CKD) has also been shown to increase the risk of allopurinol-SCAR due to excessive accumulation of oxypurinol, the renally excreted metabolite of allopurinol 4 . HLA-B*58:01 carriage and prevalence of CKD are likely contributing factors to the risk of developing SJS/TEN being five times higher in Blacks compared to Whites 5 , 6 . Despite the increased carriage rate of HLA-B*58:01 in US Blacks, HLA associations with allopurinol-SCAR in heterogenous populations in the US have not been defined. METHODS BioVU Cohorts Allopurinol tolerant controls were selected from the VUMC BioVU 7 population based on availability of MEGA EX array typing, self-reported Black or White race, age ≥ 18 years at time of allopurinol treatment, baseline creatine values available in the 30 days prior to allopurinol initiation, ≥ 90 days of allopurinol treatment (drug era length), absence of any International Classification of Diseases (ICD) codes pertaining to an allopurinol adverse reaction, and absence of an allopurinol-specific allergy label. We performed descriptive statistics on the allopurinol tolerant controls including baseline creatinine and presence of ICD codes for CKD and gout. A 10:1 case:control match by age, sex, and self-reported race to allopurinol-SCAR cases was performed through optimal pair matching using the MatchIt R package 8 . Allopurinol-SCAR Cases Consenting patients (n=14) with specialist adjudicated allopurinol-SCAR were prospectively recruited between 2015-2024 under institutional review board (IRB) approval from VUMC IRB (131836, 150754, and 171900). Specialist adjudicated SJS/TEN patients (n=2) were identified cross-sectionally in the SJS survivor research study who had developed SJS/TEN between 2009-2017 and participated in 2020-2024 under VUM IRB approval (191350). HLA Typing HLA class I and II alleles from BioVU participants were imputed from MEGA EX using SNP2HLA to 4 digit resolution 9 . High-resolution typing of HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, and HLA-DR of allopurinol-SCAR cases was performed using sequence-based typing via Illumina MiSeq as previously described 10 . Statistical Analyses The conditional logistic regression of HLA class I and II alleles comparing allopurinol-SCAR cases to 10:1 matched, allopurinol tolerant controls was performed with the MatchIt and MiDAS R packages 11 . HLA class I and II alleles meeting the unadjusted P <.05 along with their odds ratio (OR), 95% confidence intervals (CI), and Bonferroni corrected P values ( Pc ) were reported. For alleles with Pc <.05, we further compared allopurinol-SCAR cases with BioVU population controls, including self-identified Black, self-identified White, and overall populations by Fisher’s exact test. To evaluate for gene-dose effect of HLA-B*58:01, we performed Fisher’s exact test and calculated OR and 95% CI with Haldane’s modification for heterozygous and homozygous genotypes 12 . We performed drug era persistence analyses in the allopurinol tolerant controls (10:1 matched for risk allele carriage by age, gender, and race) for significant alleles to evaluate any differences in reaching 180 days of treatment using the ggsurvfit R package 13 . RESULTS We identified 16 patients diagnosed with allopurinol-SCAR with high-resolution HLA typing ( eTable 1 ) where a total of 11 (69%) cases self-identified as Black and 5 (31%) as White ( Table 1 ). We identified 1,122 allopurinol tolerant controls from BioVU ( eFigure 1 ) and those of self-identified Black race had higher baseline creatinine values (1.76 mg/dL vs 1.46, mg/dL, P <.001) and occurrence of ICD codes corresponding to CKD (90% vs 74%, P <.001) compared to those of self-identified White race ( eTable 2 ). From the allopurinol tolerant controls, we identified 160 individuals matched (10:1) by age, gender, and race. View this table: View inline View popup Download powerpoint Table 1: Summary of the allopurinol-associated SCAR case cohort demographics, HLA risk allele carriage, and clinical characteristics. From our case-control conditional logistic regression analysis, we found two HLA class I alleles independently associated with increased risk of allopurinol-SCAR: HLA-B*58:01 (OR 28 [95% CI, 8.6 – 100.6], Pc <.001) and HLA-A*34:02 (OR 20.6 [95% CI, 3.3 – 131.1], Pc =.04) ( Table 2 ) while HLA-B*35:01 and HLA-B*58:02 had unadjusted P <.05. We did not identify any HLA class II alleles meeting the unadjusted P or Pc levels of significance. Carriage of HLA-B*58:01 ( Figure 1A ) was higher in the allopurinol-SCAR cases (62.5%) compared to the allopurinol tolerant matched controls (5.6%, P <.001) and the BioVU overall population (2.3%, P <.001). Carriage of HLA-A*34:02 ( Figure 1B ) was also higher in the allopurinol-SCAR cases (18.8%) compared to the allopurinol tolerant matched controls (4.4%, P =.05) and the BioVU overall population (1.3%, P =.001). Homozygosity at HLA-B*58:01 was associated with a higher risk of developing allopurinol-SCAR (OR 55.3 [95% CI, 2.5-1208.6]) compared to heterozygosity in HLA-B*58:01 ( eTable 3 ). Drug era persistence analyses showed no difference in allopurinol tolerant controls with and without HLA-B*58:01 ( eFigure 2A ) or HLA-A*34:02 reaching a drug era length of 180 days ( eFigure 2B ). Download figure Open in new tab Figure 1: HLA-B*58:01 and HLA-A34:02 carriage are increased in allopurinol-SCAR (A ) Percentage of HLA-B*58:01 positive individuals for each described population. (B) Percentage of HLA-A*34:02 positive individuals for each described population. View this table: View inline View popup Download powerpoint Table 2: HLA-B*58:01 and HLA-A*34:02 are significantly associated with allopurinol-SCAR. Conditional logistic regression analysis for HLA class I to compare allopurinol-SCAR cases and allopurinol tolerant (10:1) matched controls (matched for age, gender, race). DISCUSSION We are the first to demonstrate that HLA-B*58:01 is strongly associated with allopurinol-SCAR in a predominantly self-identified US Black population. Homozygosity at HLA-B*58:01 appeared to confer particularly high risk, suggesting a potential gene-dose effect in this population. HLA-A*34:02, an allele associated with allopurinol-induced drug-induced liver injury (DILI), a condition with phenotypic overlap with DRESS 14 , emerged as an additional risk factor for allopurinol-SCAR. HLA-B*35:01, an allele with no previous linkage to allopurinol-SCAR, also appeared to be a potential additional risk factor; however future studies are needed to validate this finding. We also observed a single case of allopurinol-SCAR that carried HLA-B*58:02, an allele closely related to HLA-B*58:01 which would not be detected by HLA-B*58:01 specific testing. Importantly, carriage of HLA-B*58:01, HLA-B*58:02, HLA-A*34:02, and HLA-B*35:01 accounted for 100% of allopurinol-SCAR cases in our patient cohort. This finding suggests that multiple allele testing would more accurately identify representative risk in a heterogenous population 15 . Additionally, this study also demonstrated that those of self-identified Black race exhibited more clinical risk factors such as increased baseline creatine values and prevalence of CKD compared to those of self-identified White race, highlighting clinical factors also associated with allopurinol-SCAR. Limitations While the number of allopurinol-SCAR cases in this study is small, this limitation is offset by the clinical relevance of the population studied which highlights the overrepresentation of CKD and HLA-B*58:01 carriage in Black versus White populations in the US. The ability to determine these associations despite the small sample size and rarity of SCAR reflects upon high effects sizes and the notable safety finding that screening for HLA-B*58:01 alone would miss one-third of allopurinol-SCAR cases in US populations. CONCLUSIONS In our primarily self-identified Black US population, we replicated the established association of HLA-B*58:01 and identified HLA-A*34:02 as a novel risk factor for allopurinol-SCAR. HLA-B*58:01 and CKD are both independently associated with increased risk and are overrepresented in Black populations, underscoring the convergence of genetic susceptibility and the impact of social and structural determinants of health. The established risk allele HLA-B*58:01 was absent in over one-third of patients with allopurinol-SCAR, highlighting the need to expand our understanding of additional genetic and host factors that contribute to risk. These findings support the necessity of population-based studies aiming to mitigate harm among those most vulnerable to these severe, life-threatening reactions. Author Contributions All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. CNC and MSK contributed equally to the work. Acquisition of original cohort : EJP Concept and design : CNC, MSK, EJP Acquisition, analysis, or interpretation of data : CNC, MSK, AY, EJP Drafting of the manuscript : CNC, MSK Critical review of the manuscript for important intellectual content : CNC, MSK, EJP Statistical analysis : MSK Obtained funding : EJP Administrative, technical, or material support : AY, EJP Supervision : EJP Conflict of Interest Disclosures All authors have no conflict of interest to declare relevant to the content of this article. EJP receives royalties and consulting fees from UpToDate (where she is a Drug Allergy Section Editor) and has received consulting fees from Janssen, Verve, Servier, Rapt, Esperion, Elion and Glenmark. EJP is the co-director of IIID Pty Ltd, which holds a patent for HLA-B*57:01 testing for abacavir hypersensitivity and EJP holds a patent for detection of HLA A*32:01 in connection with diagnosing DRESS symptoms; however, EJP does not receive any financial remuneration for these patents, and neither are related to the submitted work. Funding/Support This work was supported by the NIH R01HG010863, P50GM115305, K08AI185260 as well as the AAAAI Foundation, Angela Anderson Research Fund, and SJS Research Fund. Role of the Funder/Sponsor The funding organizations had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. Data Sharing Statement De-identified clinical data and high-resolution HLA sequencing will be made available to all investigators with or without existing support. Data Availability De-identified clinical data and high resolution HLA sequencing will be made available upon request to the corresponding author. FIGURE LEGENDS Download figure Open in new tab eFigure 1. Consort diagram illustrating inclusion criteria for the BioVU overall population and allopurinol tolerant controls. Download figure Open in new tab eFigure 2: There is no difference in drug era length for allopurinol tolerant controls carrying HLA-B*58:01 or HLA-A*34:02 compared to allopurinol tolerant controls that do not carry the respective HLA alleles. (A) Survival analysis for a drug era length of 180 days comparing allopurinol tolerant controls that are either HLA-B*58:01 positive or negative. (B) Survival analysis for a drug era length of 180 days comparing allopurinol tolerant controls that are either HLA-A*34:02 positive or negative. View this table: View inline View popup Download powerpoint eTable 1: Complete HLA carriage of the allopurinol-SCAR cases cohort. High-resolution HLA typing was performed by Illumina MiSeq as previously published by sequencing of the Exon 2,3 region of HLA Class I and HLA-DQB1 and the Exon 2 region of HLA-DRB1, DQA1, and DPB1. Reference sequences were obtained through the IMGT/HLA Sequence Database and alleles were called through IIID HLA Analysis Suite. NP, allele not present. View this table: View inline View popup Download powerpoint eTable 2: Characteristic summary of the BioVU allopurinol tolerant control cohort according to self-identified race. View this table: View inline View popup Download powerpoint eTable 3: Homozygosity at HLA-B*58:01 increases risk of allopurinol-SCAR. Fisher’s exact test and calculated OR and 95% CI with Haldane’s modification for heterozygosity and homozygosity at HLA-B*58:01 to evaluate gene-dose effect. Acknowledgements We gratefully thank and acknowledge the community of SJS/TEN and DRESS patients for their participation in this study. We would like to thank the staff of the Vanderbilt Institute for Clinical and Translational Research, supported by NIH UL1TR002243, for maintaining BioVU and Synthetic Derivative from which the allopurinol tolerant and population controls were derived. We acknowledge the Immunogenetic Microbial Genomics and Single Cell Technologies Core (IMGSCT) at VUMC and the Institute for Immunology and Infectious Diseases (A. Chopra), Murdoch University, Murdoch Western Australia for the provision of class I and II HLA typing. SJS Survivor Study: Elizabeth J Phillips, MD (PI), Roni Dodiuk Gad, MD, Aaron Drucker, MD, Elizabeth Ergen, MD, Michelle Goh MBBS, Benjamin Kaffenberger, MD, Robert Micheletti, MD, Rama Gangula, MS, Rebecca Lee, Dana King, Kelby Mahan, Michelle Martin-Pozo, PhD, April O’Connor, Amy Palubinksy, PhD, Suman Pakala, ME, Kristina Williams, Elizabeth Williams, MPH REFERENCES 1. ↵ Hung SI , Chung WH , Liou LB , et al. 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Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following HLA-B*58:01 is an Incomplete Predictor of Allopurinol-Induced Severe Cutaneous Adverse Reactions Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share HLA-B*58:01 is an Incomplete Predictor of Allopurinol-Induced Severe Cutaneous Adverse Reactions Chelsea N. Campbell , Matthew S. Krantz , Alexis Yu , Elizabeth J. Phillips , the SJS Survivor Study medRxiv 2025.05.23.25328236; doi: https://doi.org/10.1101/2025.05.23.25328236 Share This Article: Copy Citation Tools HLA-B*58:01 is an Incomplete Predictor of Allopurinol-Induced Severe Cutaneous Adverse Reactions Chelsea N. Campbell , Matthew S. 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