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

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

doi:10.1136/annrheumdis-2021-220578

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

Ann Rheum Dis. 2022 Mar;81(3):406-415. doi: 10.1136/annrheumdis-2021-220578. Epub 2021 Nov 17.

Authors

Vivian E Saper^#¹, Michael J Ombrello^#², Adriana H Tremoulet³, Gonzalo Montero-Martin⁴, Sampath Prahalad^{5

6}, Scott Canna⁷, Chisato Shimizu³, Gail Deutsch⁸, Serena Y Tan⁹, Elaine F Remmers¹⁰, Dimitri Monos¹¹, Timothy Hahn¹², Omkar K Phadke⁶, Elaine Cassidy⁷, Ian Ferguson¹³, Vamsee Mallajosyula¹⁴, Jianpeng Xu¹⁵, Jaime S Rosa Duque¹⁶, Gilbert T Chua¹⁶, Debopam Ghosh¹⁵, Ann Marie Szymanski², Danielle Rubin², Jane C Burns³, Lu Tian¹⁷, Marcelo A Fernandez-Vina⁴, Elizabeth D Mellins^#¹, Jill A Hollenbach^#¹⁸; Drug Hypersensitivity Consortium; INCHARGE Consortium

Collaborators

Rabheh Abdul Aziz, Roberta Berard, Catherine A Bingham, Alexis D Bonaparth, Alicia Casey, Kathleen P Collins, Michal Cidon, Steven I Goodman, Alexei A Grom, Melissa Hazen, Alice Hoftman, Maria Ibarra, Rita Jerath, Daniel J Kingsbury, Marisa S Klein-Gitelman, Khanh Lai, Sivia Lapidus, Roberto Mendoza-Londono, Karen Onel, Maria Perez, Suhas M Radhakrishna, Adam Reinhardt, Mona Riskalla, Johannes Roth, Natalie Rosenwasser, Nadine Saad, Grant S Schulert, Susan Shenoi, Judith A Smith, Jennifer Soep, Cory Stingl, Matthew L Stoll, Melissa Tesher, Benjamin Whitehead, Lawrence Zemel, Jordi Anton, John F Bohnsack, Joanna Cobb, Erkan Demirkaya, Dirk Foell, Marco Gattorno, Alexei Grom, Maria Odete Hilario, Norman T Ilowite, Johannes-Peter Haas, Anne Hinks, Daniel L Kastner, Carl D Langfeld, Alberto Martini, Elizabeth D Mellins, Kirsten Minden, Sheila Oliveira, Michael J Ombrello, Seza Özen, Sampath Prahalad, Angela Rosen-Wolff, Alan Rosenberg, Ricardo Russo, Sara Signa, Ioanna Tachmazidou, Klaus Tenbrock, Susan Thompson, Wendy Thomson, Lucy R Wedderburn, Patricia Woo, Rae S M Yeung, Andrew S Zeft, Claudio Len

Affiliations

¹ Pediatrics, Stanford University, Stanford, California, USA vesaper@stanford.edu mellins@stanford.edu.
² Translational Genetics and Genomics Unit, NIAMS, National Institutes of Health, Bethesda, Maryland, USA.
³ Pediatrics, University of California San Diego, La Jolla, California, USA.
⁴ Stanford Blood Center, Histocompatibility and Immunogenetics Laboratory, Stanford University, Stanford, California, USA.
⁵ Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
⁶ Pediatrics, Emory University, Atlanta, Georgia, USA.
⁷ Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁸ Pathology, Seattle Children's Hospital, Seattle, Washington, USA.
⁹ Pathology, Stanford University, Stanford, California, USA.
¹⁰ National Human Genome Research Institute, Bethesda, Maryland, USA.
¹¹ Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹² Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
¹³ Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
¹⁴ Microbiology and Immunology, Stanford University, Stanford, California, USA.
¹⁵ Pediatrics, Stanford University, Stanford, California, USA.
¹⁶ Pediatrics, University of Hong Kong, Hong Kong Special Adminstrative District, China.
¹⁷ Biomedical Data Science, Stanford University, Stanford, California, USA.
¹⁸ Neurology, University of California San Francisco, San Francisco, California, USA.

^# Contributed equally.

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.

Keywords: Still's disease; adult-onset; arthritis; biological therapy; juvenile; pharmacogenetics.

Publication types

Multicenter Study
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding