Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB115 alleles

• Type of Material: Article
• Authors: vivian e. Saper, Stanford University; Michael J. Ombrello, National Institute of Arthritis and Musculoskeletal and Skin Diseases; Adriana H. Tremoulet, University of California, San Diego; Gonzalo Montero-Martin, Stanford University; Sampath Prahalad, Emory University; Scott Canna, University of Pittsburgh; Chisato Shimizu, University of California, San Diego; Gail Deutsch, University of Washington, Seattle; Serena Tan, Stanford University; Elaine F. Remmers, National Human Genome Research Institute; Dimitri Monos, University of Pennsylvania; Timothy Hahn, Pennsylvania State University, Hershey; Omkar K. Phadke, Emory University; Elaine A. Cassidy, University of Pittsburgh; Ian D. Ferguson, Yale University; Vamsee Mallajosyula, Stanford University; Jianpeng Xu, Stanford University; Jaime S. Rosa Duque, The University of Hong Kong; Gilbert T. Chua, The University of Hong Kong; Debopam Ghosh, Stanford University; Ann Marie Szymanski, National Institute of Arthritis and Musculoskeletal and Skin Diseases; Danielle Rubin, National Institute of Arthritis and Musculoskeletal and Skin Diseases; Jane C. Burns, University of California, San Diego; Lu tian, Stanford University; Marcelo A. Fernandez-Vina, Stanford University; Elizabeth D. Mellins, Stanford University; Jill A. Hollenbach, University of California, San Francisco
• Language: English
• Date: 2021-11-17
• Publisher: BMJ
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © Author(s) (or their employer(s)) 2022
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): https://doi.org/10.1136/annrheumdis-2021-220578
• Title of Journal or Parent Work: Annals of the Rheumatic Diseases
• Volume: 81
• Issue: 3
• Start Page: 406
• End Page: 415
• Grant/Funding Information: This work was funded by The Lucile Packard Foundation for Children’s Health, Stanford Maternal and Child Health Research Institute, the Division of Intramural Research of the National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases [Z01-AR041198] and National Human Genome Research Institute [Z01-HG200370]), the Gordon and Marilyn Macklin Foundation, RK Mellon Institute for Pediatric Research, and The Marcus Foundation Inc., Atlanta, GA. This study utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).
• Keywords: Juvenile Arthritis; Pharmacogenetics; Still’s disease; Biologic Therapy
• Research Categories: Biology, Genetics; Health Sciences, Immunology; Health Sciences, Pharmacology

Abstract

Objectives: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or interleukin 6 (IL-6) in a small group of Still’s patients with atypical lung disease. We sought to characterize features of Still’s patients with DRESS compared to drug-tolerant Still’s controls. We analyzed human leukocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort. Methods: In a case/control study, we collected a multicenter series of Still’s patients with features of inhibitor-related DRESS (n=66) and drug-tolerant Still’s controls (n=65). We retrospectively analyzed clinical data from all Still’s subjects and HLA-typed 94/131. European Still’s-DRESS cases were ancestry-matched to INCHARGE pediatric Still’s cases (n=550) and compared for HLA allele frequencies. HLA association also was analyzed using Still’s-DRESS cases (n=64) compared to drug-tolerant Still’s controls (n=30). KD subjects (n=19) were similarly studied. Results: Still’s-DRESS features included eosinophilia (89%), AST-ALT elevation (75%), and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still’s-DRESS (64%) versus drug-tolerant Still’s (3%; p=1.9×10−14). We found striking enrichment for HLA-DRB1*15 haplotypes in Still’s-DRESS cases versus INCHARGE Still’s controls (p=7.5×10−13) and versus self-identified, ancestry-matched Still’s controls (p=6.3×10−10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions. Conclusions: DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of pre-prescription HLA typing and vigilance for serious reactions to these drugs are warranted.