HLA-B Alleles With Shared Peptide Binding Specificities Define Global Risk of Co-trimoxazole-Induced Severe Cutaneous Adverse Drug Reactions

Yueran Li; Andrew Gibson; Hajirah N Saeed; Mohammadali Ashraf; Danmeng Li; David A Ostrov; Matthew S Krantz; Simon A Mallal; Eric Alves; Abha Chopra; Linda Choo; Roni P Dodiuk-Gad; Benjamin Kaffenberger; Aaron M Drucker; Michelle S Goh; Elizabeth Ergen; Robert Micheletti; Misha Rosenbach; Michelle D Martin-Pozo; Rama Gangula; Elizabeth A Williams; Alexis Yu; April O'Connor; Kelby Mahan; James T Kwan; Derek Metcalfe; Ramy Rashad; Swapna S Shanbhag; Mohammed Ali Tahboub; Sarah Pedretti; Phuti Choshi; Tafadzwa Chimbetete; Rose Selim; Ian James; Jason A Trubiano; Rannakoe Lehloenya; Jonny G Peter; Elizabeth J Phillips; SJS Survivor Study

doi:10.1016/j.jaip.2025.08.001

HLA-B Alleles With Shared Peptide Binding Specificities Define Global Risk of Co-trimoxazole-Induced Severe Cutaneous Adverse Drug Reactions

J Allergy Clin Immunol Pract. 2025 Aug 8:S2213-2198(25)00762-7. doi: 10.1016/j.jaip.2025.08.001. Online ahead of print.

Authors

Yueran Li¹, Andrew Gibson¹, Hajirah N Saeed², Mohammadali Ashraf³, Danmeng Li⁴, David A Ostrov⁵, Matthew S Krantz⁶, Simon A Mallal⁷, Eric Alves¹, Abha Chopra¹, Linda Choo¹, Roni P Dodiuk-Gad⁸, Benjamin Kaffenberger⁹, Aaron M Drucker¹⁰, Michelle S Goh¹¹, Elizabeth Ergen¹², Robert Micheletti¹³, Misha Rosenbach¹³, Michelle D Martin-Pozo⁶, Rama Gangula⁶, Elizabeth A Williams⁶, Alexis Yu⁶, April O'Connor⁶, Kelby Mahan⁶, James T Kwan¹⁴, Derek Metcalfe¹⁴, Ramy Rashad¹⁴, Swapna S Shanbhag¹⁵, Mohammed Ali Tahboub¹⁴, Sarah Pedretti¹⁶, Phuti Choshi¹⁷, Tafadzwa Chimbetete¹⁷, Rose Selim¹⁷, Ian James¹, Jason A Trubiano¹⁸, Rannakoe Lehloenya¹⁹, Jonny G Peter²⁰, Elizabeth J Phillips²¹; SJS Survivor Study

Affiliations

¹ Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
² Department of Ophthalmology, Massachusetts Eye and Ear Institute, Harvard Medical School, Boston, Mass; Department of Ophthalmology, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Ill.
³ Department of Ophthalmology, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Ill.
⁴ Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, Fla.
⁵ Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Fla.
⁶ Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tenn.
⁷ Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tenn.
⁸ Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel; Department of Dermatology, Emek Medical Center, Afula, Israel; Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁹ Department of Dermatology, Ohio State University Wexner Medical Center, Columbus, Ohio.
¹⁰ Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Medicine and Women's College Research and Innovation Institute, Women's College Hospital, Toronto, Ontario, Canada.
¹¹ Department of Dermatology, Austin Health, Heidelberg, Victoria, Australia; Department of Dermatology, Alfred Health, Melbourne, Victoria, Australia; Department of Dermatology, St Vincent's Hospital, Melbourne, Victoria, Australia.
¹² Department of Medicine, University of Tennessee, Knoxville, Tenn.
¹³ Department of Dermatology, University of Pennsylvania, Philadelphia, Pa.
¹⁴ Department of Ophthalmology, Massachusetts Eye and Ear Institute, Harvard Medical School, Boston, Mass.
¹⁵ Department of Ophthalmology, Massachusetts Eye and Ear Institute, Harvard Medical School, Boston, Mass; The Cornea Institute, LV Prasad Eye Institute, Hyderabad, Telangana, India.
¹⁶ Allergy and Immunology Unit, University of Cape Town Lung Institute, Cape Town, South Africa.
¹⁷ Division of Allergy and Clinical Immunology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
¹⁸ Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia; Centre for Antibiotic Allergy and Research, Austin Health, Melbourne, Victoria, Australia.
¹⁹ Division of Dermatology, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
²⁰ Allergy and Immunology Unit, University of Cape Town Lung Institute, Cape Town, South Africa; Division of Allergy and Clinical Immunology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
²¹ Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tenn. Electronic address: elizabeth.j.phillips@vumc.org.

PMID: 40784610
PMCID: PMC12541198 (available on 2026-08-08)
DOI: 10.1016/j.jaip.2025.08.001

Abstract

Background: Co-trimoxazole is a leading global cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Co-trimoxazole-induced SCAR are associated with HLA class I alleles including HLA-B∗13:01 and HLA-B∗38:02 in Southeast Asian (SEA) populations. However, the global generalizability of these associations is unknown but critical for population-appropriate risk stratification and diagnosis.

Objective: To determine HLA risk factors associated with co-trimoxazole-induced SJS/TEN and DRESS in populations from the United States and South Africa.

Methods: We performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced patients with SCAR in the United States (n = 63) and South Africa (n = 26) compared with population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2.

Results: In a multiple logistic regression model, HLA-B^∗44:03 (corrected P [Pc] < .001; odds ratio [OR] = 4.08), HLA-B^∗38:01 (Pc < .001; OR = 5.66), and HLA-C^∗04:01 (Pc = .003; OR = 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the United States. HLA-B^∗44:03 was also associated with co-trimoxazole-induced DRESS in South Africa (Pc = .019; OR = 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C^∗04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the United States, respectively. The SEA risk allele HLA-B^∗13:01, with SPBS to HLA-B^∗44:03, was identified in just one of 63 US patients with SCAR.

Conclusions: HLA alleles with SPBS to SEA-related risk alleles, including HLA-B^∗44:03 (SPBS with HLA-B^∗13:01) and HLA-B^∗38:01 (SPBS with HLA-B^∗38:02) but also HLA-C^∗04:01, predisposed to co-trimoxazole-induced SCAR in the United States and South Africa. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR.

Keywords: Co-trimoxazole; Drug reaction with eosinophilia and systemic symptoms; HLA; Severe cutaneous adverse drug reaction; Stevens-Johnson syndrome and toxic epidermal necrolysis.

Abstract

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