Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles.

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 IL-6 in a small group of patients with Still's disease with atypical lung disease. We sought to characterise features of patients with Still's disease with DRESS compared with drug-tolerant Still's controls. We analysed human leucocyte 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 multicentre series of patients with Still's disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still's controls (n=65). We retrospectively analysed clinical data from all Still's subjects and typed 94/131 for HLA. European Still's-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still's cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still's-DRESS cases (n=64) compared with 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=1.2×10-14). 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 preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.

• Authors: Vivian E Saper, Michael J Ombrello, Adriana H Tremoulet, Gonzalo Montero-Martin, Sampath Prahalad, Scott Canna, Chisato Shimizu, Gail Deutsch, Serena Y Tan, Elaine F Remmers, Dimitri Monos, Timothy Hahn, Omkar K Phadke, Elaine Cassidy, Ian Ferguson, Vamsee Mallajosyula, Jianpeng Xu, Jaime S Rosa Duque, Gilbert T Chua, Debopam Ghosh, Ann Marie Szymanski, Danielle Rubin, Jane C Burns, Lu Tian, Marcelo A Fernandez-Vina, Elizabeth D Mellins, Jill A Hollenbach, Drug Hypersensitivity Consortium, INCHARGE Consortium
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 81 Issue 3 Pg. 406-415 (03 2022) ISSN: 1468-2060 [Electronic] England
• PMID: 34789453 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antirheumatic Agents
• HLA-DRB1 Chains
• Interleukin-1
• Interleukin-6

Topics

• Adult
• Alleles
• Antirheumatic Agents (adverse effects)
• Case-Control Studies
• Drug Hypersensitivity Syndrome (genetics, immunology)
• Drug Tolerance (genetics)
• Female
• HLA-DRB1 Chains (genetics, immunology)
• Haplotypes
• Humans
• Hypersensitivity, Delayed (genetics, immunology)
• Interleukin-1 (antagonists & inhibitors)
• Interleukin-6 (antagonists & inhibitors)
• Male
• Mucocutaneous Lymph Node Syndrome (drug therapy, genetics)
• Retrospective Studies
• Still's Disease, Adult-Onset (drug therapy, genetics, immunology)