Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles. Issue 3 (17th November 2021)

• Record Type: Journal Article
• Authors: Saper, Vivian E; Ombrello, Michael J; Tremoulet, Adriana H; Montero-Martin, Gonzalo; Prahalad, Sampath; Canna, Scott; Shimizu, Chisato; Deutsch, Gail; Tan, Serena Y; Remmers, Elaine F; Monos, Dimitri; Hahn, Timothy; Phadke, Omkar K; Cassidy, Elaine; Ferguson, Ian; Mallajosyula, Vamsee; Xu, Jianpeng; Rosa Duque, Jaime S; Chua, Gilbert T; Ghosh, Debopam; Szymanski, Ann Marie; Rubin, Danielle; Burns, Jane C; Tian, Lu; Fernandez-Vina, Marcelo A; Mellins, Elizabeth D; Hollenbach, Jill A
• Other Names: author non-byline.; Aziz Rabheh Abdul author non-byline.; Berard Roberta author non-byline.; Bingham Catherine A author non-byline.; Bonaparth Alexis D author non-byline.; Casey Alicia author non-byline.; Collins Kathleen P author non-byline.; Cidon Michal author non-byline.; Goodman Steven I author non-byline.; Grom Alexei A author non-byline.; Hazen Melissa author non-byline.; Hoftman Alice author non-byline.; Ibarra Maria author non-byline.; Jerath Rita author non-byline.; Kingsbury Daniel J author non-byline.; Klein-Gitelman Marisa S author non-byline.; Lai Khanh author non-byline.; Lapidus Sivia author non-byline.; Mendoza-Londono Roberto author non-byline.; Onel Karen author non-byline.; Perez Maria author non-byline.; Radhakrishna Suhas M author non-byline.; Reinhardt Adam author non-byline.; Riskalla Mona author non-byline.; Roth Johannes author non-byline.; Rosenwasser Natalie author non-byline.; Saad Nadine author non-byline.; Schulert Grant S author non-byline.; Shenoi Susan author non-byline.; Smith Judith A author non-byline.; Soep Jennifer author non-byline.; Stingl Cory author non-byline.; Stoll Matthew L author non-byline.; Tesher Melissa author non-byline.; Whitehead Benjamin author non-byline.; Zemel Lawrence author non-byline.; author non-byline.; Anton Jordi author non-byline.; Bohnsack John F author non-byline.; Cobb Joanna author non-byline.; Demirkaya Erkan author non-byline.; Foell Dirk author non-byline.; Gattorno Marco author non-byline.; Grom Alexei author non-byline.; Hilario Maria Odete author non-byline.; Ilowite Norman T author non-byline.; Haas Johannes-Peter author non-byline.; Hinks Anne author non-byline.; Kastner Daniel L author non-byline.; Langfeld Carl D author non-byline.; Martini Alberto author non-byline.; Mellins Elizabeth D author non-byline.; Minden Kirsten author non-byline.; Oliveira Sheila author non-byline.; Ombrello Michael J author non-byline.; Özen Seza author non-byline.; Prahalad Sampath author non-byline.; Rosen-Wolff Angela author non-byline.; Rosenberg Alan author non-byline.; Russo Ricardo author non-byline.; Signa Sara author non-byline.; Tachmazidou Ioanna author non-byline.; Tenbrock Klaus author non-byline.; Thompson Susan author non-byline.; Thomson Wendy author non-byline.; Wedderburn Lucy R author non-byline.; Woo Patricia author non-byline.; Yeung Rae S M author non-byline.; Zeft Andrew S author non-byline.; Len Claudio author non-byline.;
• Is Part Of: Annals of the rheumatic diseases. Volume 81:Issue 3(2022)
• Page Start: 406
• Page End: 415
• Publication Date: 2021-11-17
• Subjects: pharmacogenetics -- biological therapy -- arthritis -- juvenile -- Still's disease -- adult-onset; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2021-220578
• Languages: English
• ISSNs: 0003-4967

Abstract

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.