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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| Published in | Annals of the rheumatic diseases Vol. 81; no. 3; pp. 406 - 415 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
BMJ Publishing Group Ltd and European League Against Rheumatism
01.03.2022
Elsevier Limited |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0003-4967 1468-2060 1468-2060 |
| DOI | 10.1136/annrheumdis-2021-220578 |
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| Abstract | 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-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.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. |
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| AbstractList | 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.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.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.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.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.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-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.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.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. 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-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.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. 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. 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. 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 ). We found striking enrichment for HLA-DRB1*15 haplotypes in Still's-DRESS cases versus INCHARGE Still's controls (p=7.5×10 ) and versus self-identified, ancestry-matched Still's controls (p=6.3×10 ). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions. 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. |
| Author | Grom, Alexei A Saper, Vivian E Prahalad, Sampath Hollenbach, Jill A Remmers, Elaine F Tremoulet, Adriana H Smith, Judith A Collins, Kathleen P Szymanski, Ann Marie Roth, Johannes Schulert, Grant S Montero-Martin, Gonzalo Zemel, Lawrence Tenbrock, Klaus Hazen, Melissa Mellins, Elizabeth D Xu, Jianpeng Goodman, Steven I Shenoi, Susan Özen, Seza Burns, Jane C Stingl, Cory Rosenberg, Alan Casey, Alicia Soep, Jennifer Deutsch, Gail Len, Claudio Rosa Duque, Jaime S Bingham, Catherine A Mendoza-Londono, Roberto Radhakrishna, Suhas M Monos, Dimitri Minden, Kirsten Kastner, Daniel L Yeung, Rae S M Saad, Nadine Tachmazidou, Ioanna Wedderburn, Lucy R Oliveira, Sheila Lai, Khanh Reinhardt, Adam Woo, Patricia Hoftman, Alice Cobb, Joanna Bohnsack, John F Hahn, Timothy Anton, Jordi Ferguson, Ian Chua, Gilbert T Canna, Scott Ombrello, Michael J Mallajosyula, Vamsee Hinks, Anne Onel, Karen Foell, Dirk Gattorno, Marco Martini, Alberto Langfeld, Carl D Tesher, Melissa Grom, Alexei Lapidus, Sivia Tan, Serena Y Rubin, Danielle Tian, Lu Aziz, Rabheh Abdul Klein-Gitelman, |
| AuthorAffiliation | 6 University of Washington, Seattle, WA 8 University of Pennsylvania, Philadelphia, PA 2 National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 1 Stanford University, Stanford, CA 9 Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA 10 Yale University Medical School, New Haven, Connecticut, USA 5 University of Pittsburgh, Pittsburgh, PA 7 National Human Genome Research Institute, Bethesda, MD 11 The University of Hong Kong, Hong Kong Special Administrative Region, China 12 University of California San Francisco, San Francisco, CA 3 University of California San Diego, San Diego, CA 4 Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA |
| AuthorAffiliation_xml | – name: 1 Stanford University, Stanford, CA – name: 5 University of Pittsburgh, Pittsburgh, PA – name: 6 University of Washington, Seattle, WA – name: 3 University of California San Diego, San Diego, CA – name: 12 University of California San Francisco, San Francisco, CA – name: 4 Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA – name: 7 National Human Genome Research Institute, Bethesda, MD – name: 11 The University of Hong Kong, Hong Kong Special Administrative Region, China – name: 9 Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA – name: 2 National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD – name: 10 Yale University Medical School, New Haven, Connecticut, USA – name: 8 University of Pennsylvania, Philadelphia, PA |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34789453$$D View this record in MEDLINE/PubMed |
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| Copyright | Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ. 2022 Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ. |
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| DOI | 10.1136/annrheumdis-2021-220578 |
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| Keywords | Still's disease adult-onset juvenile arthritis biological therapy pharmacogenetics |
| Language | English |
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| Notes | 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. |
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| Publisher | BMJ Publishing Group Ltd and European League Against Rheumatism Elsevier Limited |
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| Snippet | ObjectivesDrug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors... Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of... |
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| StartPage | 406 |
| SubjectTerms | 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 |
| Title | Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB115 alleles |
| URI | https://ard.bmj.com/content/81/3/406.full https://www.ncbi.nlm.nih.gov/pubmed/34789453 https://www.proquest.com/docview/2628421346 https://www.proquest.com/docview/2599075599 https://pubmed.ncbi.nlm.nih.gov/PMC10564446 |
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