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

ObjectivesDrug 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 featur...

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Veröffentlicht in:	Annals of the rheumatic diseases Jg. 81; H. 3; S. 406 - 415
Hauptverfasser:	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, Aziz, Rabheh Abdul, Berard, Roberta, Bingham, Catherine A, Bonaparth, Alexis D, Casey, Alicia, Collins, Kathleen P, Cidon, Michal, Goodman, Steven I, Grom, Alexei A, Hazen, Melissa, Hoftman, Alice, Ibarra, Maria, Jerath, Rita, Kingsbury, Daniel J, Klein-Gitelman, Marisa S, Lai, Khanh, Lapidus, Sivia, Mendoza-Londono, Roberto, Onel, Karen, Perez, Maria, Radhakrishna, Suhas M, Reinhardt, Adam, Riskalla, Mona, Roth, Johannes, Rosenwasser, Natalie, Saad, Nadine, Schulert, Grant S, Shenoi, Susan, Smith, Judith A, Soep, Jennifer, Stingl, Cory, Stoll, Matthew L, Tesher, Melissa, Whitehead, Benjamin, Zemel, Lawrence, Anton, Jordi, Bohnsack, John F, Cobb, Joanna, Demirkaya, Erkan, Foell, Dirk, Gattorno, Marco, Grom, Alexei, Hilario, Maria Odete, Ilowite, Norman T, Haas, Johannes-Peter, Hinks, Anne, Kastner, Daniel L, Langfeld, Carl D, Martini, Alberto, Minden, Kirsten, Oliveira, Sheila, Özen, Seza, Rosen-Wolff, Angela, Rosenberg, Alan, Russo, Ricardo, Signa, Sara, Tachmazidou, Ioanna, Tenbrock, Klaus, Thompson, Susan, Thomson, Wendy, Wedderburn, Lucy R, Woo, Patricia, Yeung, Rae S M, Zeft, Andrew S, Len, Claudio
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States BMJ Publishing Group Ltd and European League Against Rheumatism 01.03.2022 Elsevier Limited
Schlagworte:	Adult adult-onset Alleles Antigens Antirheumatic Agents - adverse effects Arthritis biological therapy Case-Control Studies Cell activation Children Classification Cytokines Drb1 protein Drug Hypersensitivity Syndrome - genetics Drug Hypersensitivity Syndrome - immunology Drug Tolerance - genetics Eosinophilia Female Gene frequency Haplotypes Histocompatibility antigen HLA HLA-DRB1 Chains - genetics HLA-DRB1 Chains - immunology Humans Hypersensitivity (delayed) Hypersensitivity, Delayed - genetics Hypersensitivity, Delayed - immunology Interleukin 1 Interleukin 1 receptor antagonist Interleukin 6 Interleukin-1 - antagonists & inhibitors Interleukin-6 - antagonists & inhibitors juvenile Kawasaki disease Laboratories Lung diseases Lymphocytes Macrophages Male Mucocutaneous lymph node syndrome Mucocutaneous Lymph Node Syndrome - drug therapy Mucocutaneous Lymph Node Syndrome - genetics Patients Peptides pharmacogenetics Retrospective Studies Steroids Still's disease Still's Disease, Adult-Onset - drug therapy Still's Disease, Adult-Onset - genetics Still's Disease, Adult-Onset - immunology Tissue typing Treatment Vigilance Still's disease adult-onset juvenile arthritis biological therapy pharmacogenetics
ISSN:	0003-4967, 1468-2060, 1468-2060
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Zusammenfassung:	ObjectivesDrug 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.MethodsIn 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.ResultsStill’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-DRB115 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, DRB115:01 was present only in those with suspected anakinra reactions.ConclusionsDRESS-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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author contributions: Each author reviewed and approved the manuscript. EM, VS had full access to all data and verified the validity of all the data; VS contributed to study design, collected and analyzed clinical data, wrote and revised the manuscript; EM contributed to study design, supervised collection and analysis of data, wrote and revised the manuscript; MO contributed to study design, analysis and interpretation of HLA data, provided clinical data, genetic data and samples from NCT03510442, and wrote and revised the manuscript; JH contributed to study design, analysis and interpretation of HLA data, and wrote and revised the manuscript. AT, CS, JB, SP, SC, TH, EC, OP, A-MS, IF provided data and patient samples; GM-M, MF-V provided analysis and interpretation of HLA data; GD, ST provided images and analyses of tissue pathology; ER, DM, JX, VM, DR analyzed sequence data; LT provided statistical analysis; JD, GC provided intellectual contributions; DG provided figures. Drs. Saper and Ombrello are equally contributing, co-first authors of this work. Drs. Mellins and Hollenbach are equally contributing, co-senior authors of this work.
ISSN:	0003-4967 1468-2060 1468-2060
DOI:	10.1136/annrheumdis-2021-220578