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Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles
  1. Vivian E Saper1,
  2. Michael J Ombrello2,
  3. Adriana H Tremoulet3,
  4. Gonzalo Montero-Martin4,
  5. Sampath Prahalad5,6,
  6. Scott Canna7,
  7. Chisato Shimizu3,
  8. Gail Deutsch8,
  9. Serena Y Tan9,
  10. Elaine F Remmers10,
  11. Dimitri Monos11,
  12. Timothy Hahn12,
  13. Omkar K Phadke6,
  14. Elaine Cassidy7,
  15. Ian Ferguson13,
  16. Vamsee Mallajosyula14,
  17. Jianpeng Xu1,
  18. Jaime S Rosa Duque15,
  19. Gilbert T Chua15,
  20. Debopam Ghosh1,
  21. Ann Marie Szymanski2,
  22. Danielle Rubin2,
  23. Jane C Burns3,
  24. Lu Tian16,
  25. Marcelo A Fernandez-Vina4,
  26. Elizabeth D Mellins1,
  27. Jill A Hollenbach17,
  28. Drug Hypersensitivity Consortium
  29. INCHARGE Consortium
      1. 1Pediatrics, Stanford University, Stanford, California, USA
      2. 2Translational Genetics and Genomics Unit, NIAMS, National Institutes of Health, Bethesda, Maryland, USA
      3. 3Pediatrics, University of California San Diego, La Jolla, California, USA
      4. 4Stanford Blood Center, Histocompatibility and Immunogenetics Laboratory, Stanford University, Stanford, California, USA
      5. 5Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
      6. 6Pediatrics, Emory University, Atlanta, Georgia, USA
      7. 7Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
      8. 8Pathology, Seattle Children's Hospital, Seattle, Washington, USA
      9. 9Pathology, Stanford University, Stanford, California, USA
      10. 10National Human Genome Research Institute, Bethesda, Maryland, USA
      11. 11Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
      12. 12Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
      13. 13Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
      14. 14Microbiology and Immunology, Stanford University, Stanford, California, USA
      15. 15Pediatrics, University of Hong Kong, Hong Kong Special Adminstrative District, China
      16. 16Biomedical Data Science, Stanford University, Stanford, California, USA
      17. 17Neurology, University of California San Francisco, San Francisco, California, USA
      1. Correspondence to Dr Vivian E Saper, Pediatrics, Stanford University, Stanford, California, USA; vesaper{at}stanford.edu; Dr Elizabeth D Mellins, Pediatrics, Stanford University, Stanford, California, USA; mellins{at}stanford.edu

      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.

      • pharmacogenetics
      • biological therapy
      • arthritis
      • juvenile
      • Still's disease
      • adult-onset

      Data availability statement

      Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The INCHARGE consortium dataset, which was previously published (Ombrello MJ et al PNAS 2015) and used in silico for this study, is available through Dr Michael Ombrello.

      https://doi.org/10.1136/annrheumdis-2021-220578

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        Data availability statement

        Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The INCHARGE consortium dataset, which was previously published (Ombrello MJ et al PNAS 2015) and used in silico for this study, is available through Dr Michael Ombrello.

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        Footnotes

        • VES and MJO are joint first authors.

        • EDM and JAH are joint senior authors.

        • Handling editor Josef S Smolen

        • Twitter @prahaladpedrheum, @canna_lab

        • VES and MJO contributed equally.

        • EDM and JAH contributed equally.

        • Correction notice This article has been corrected since it published Online First. The twitter handle for Sampath Prahalad has been corrected.

        • Collaborators Drug Hypersensitivity Consortium: 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 Stoll; Melissa Tesher; Benjamin Whitehead; Lawrence Zemel; International Childhood Arthritis Genetics (INCHARGE) Consortium: Jordi Anton; John F Bohnsack; Joanna Cobb; Erkan Demirkaya; Dirk Foell; Marco Gattorno; Alexei Grom; Maria Odete E Hilario; Norman T Ilowite; Johannes-Peter Haas; Anne Hinks; Daniel L Kastner; Carl D Langfeld; Claudio Len;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.

        • Contributors Each author reviewed and approved the manuscript. EDM and VES are co-guarantors of this study, had access to the data, accept full responsibility for the work and conduct of the study and controlled the decision to publish. VES contributed to study design, collected and analysed clinical data, wrote and revised the manuscript. EDM contributed to study design, supervised collection and analysis of data, wrote and revised the manuscript. MJO 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. JAH contributed to study design, analysis and interpretation of HLA data, and wrote and revised the manuscript. AHT, CS, JCB, SP, SC, TH, EC, OKP, AMS and IF provided data and patient samples. GM-M and MAF-V provided analysis and interpretation of HLA data. GD and ST provided images and analyses of tissue pathology. EFR, DM, JX, VM and DR analyzed sequence data. LT provided statistical analysis. JSRD and GTC provided intellectual contributions. DG provided figures.

        • Funding This work was funded by The Lucile Packard Foundation for Children’s Health, Stanford Maternal and Child Health Research Institute, the Division of Intramural Research of the National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases (Z01-AR041198) and National Human Genome Research Institute (Z01-HG200370)), the Gordon and Marilyn Macklin Foundation, RK Mellon Institute for Paediatric Research, and The Marcus Foundation Inc, Atlanta, Georgia. This study utilised the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).

        • Competing interests VES, GD, report personal fees from Novartis, SP reports fees from Novartis outside the current work, SC reports personal fees from Novartis and grants from AB2 Bio, EDM reports grants from Novartis and JAH reports grant from Genentech. Drug Hypersensitivity Consortium: SL, GSS, SS and MS report personal fees from Novartis, AAG reports grants and personal fees from Novartis and grants from NovImmune. INCHARGE Consortium: No conflicts of interest.

        • Provenance and peer review Not commissioned; externally peer reviewed.

        • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.