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  • Immunome perturbation is present in patients with juvenile idiopathic arthritis who are in remission and will relapse upon anti-TNFα withdrawal

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Paediatric rheumatology
Immunome perturbation is present in patients with juvenile idiopathic arthritis who are in remission and will relapse upon anti-TNFα withdrawal
  1. Jing Yao Leong1,
  2. Phyllis Chen1,
  3. Joo Guan Yeo1,2,
  4. Fauziah Ally1,
  5. Camillus Chua1,
  6. Sharifah Nur Hazirah1,
  7. Su Li Poh1,
  8. Lu Pan1,
  9. Liyun Lai1,
  10. Elene Seck Choon Lee2,
  11. Loshinidevi D/O Thana Bathi1,
  12. Thaschawee Arkachaisri1,2,
  13. Daniel Lovell3,4,
  14. Salvatore Albani1
  15. Pediatric Rheumatology Collaborative Study Group
    1. 1 Translational Immunology Institute, Singhealth/Duke-NUS Academic Medical Centre, Singapore Health Service, Singapore, Singapore
    2. 2 Division of Medicine, KK Women's and Children's Hospital, Singapore, Singapore
    3. 3 Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
    4. 4 Department of Paediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
    1. Correspondence to Dr Jing Yao Leong, Translational Immunology Institute, Singhealth/Duke-NUS Academic Medical Centre, Singapore Health Service, Singapore, Singapore; leong.jing.yao{at}singhealth.com.sg

    Abstract

    Objectives Biologics treatment with antitumour necrosis factor alpha (TNFα) is efficacious in patients with juvenile idiopathic arthritis (JIA). Despite displaying clinical inactivity during treatment, many patients will flare on cessation of therapy. The inability to definitively discriminate patients who will relapse or continue to remain in remission after therapy withdrawal is currently a major unmet medical need. CD4 T cells have been implicated in active disease, yet how they contribute to disease persistence despite treatment is unknown.

    Methods We interrogated the circulatory reservoir of CD4+ immune subsets at the single-cell resolution with mass cytometry (cytometry by time of flight) of patients with JIA (n=20) who displayed continuous clinical inactivity for at least 6 months with anti-TNFα and were subsequently withdrawn from therapy for 8 months, and scored as relapse or remission. These patients were examined prior to therapy withdrawal for putative subsets that could discriminate relapse from remission. We verified on a separate JIA cohort (n=16) the dysregulation of these circulatory subsets 8 months into therapy withdrawal. The immunological transcriptomic signature of CD4 memory in relapse/remission patients was examined with NanoString.

    Results An inflammatory memory subset of CD3+CD4+CD45RA−TNFα+ T cells deficient in immune checkpoints (PD1−CD152−) was present in relapse patients prior to therapy withdrawal. Transcriptomic profiling reveals divergence between relapse and remission patients in disease-centric pathways involving (1) T-cell receptor activation, (2) apoptosis, (3) TNFα, (4) nuclear factor-kappa B and (5) mitogen-activated protein kinase signalling.

    Conclusions A unique discriminatory immunomic and transcriptomic signature is associated with relapse patients and may explain how relapse occurs.

    • Juvenile idiopathic arthritis (JIA)
    • mass cytometry (CyToF)
    • anti-TNFɑ
    • relapse and therapy withdrawal

    This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

    https://doi.org/10.1136/annrheumdis-2019-216059

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      Footnotes

      • Handling editor Josef S Smolen

      • Collaborators PRCSGPediatric Rheumatology Collaborative Study Group (PRCSG): Daniel J. Lovell, Anne L. Johnson, Steven J. Spalding, Beth S. Gottlieb, Paula W. Morris, Yukiko Kimura, Karen Onel, Suzanne C. Li, Alexei A. Grom, Janalee Taylor, Hermine I. Brunner, Jennifer L. Huggins, James J. Nocton, Kathleen A. Haines, Barbara S. Edelheit, Michael Shishov, Lawrence K. Jung, Calvin B. Williams, Melissa S. Tesher, Denise M. Costanzo, Lawrence S. Zemel, Jason A. Dare, Murray H. Passo, Kaleo C. Ede, Judyann C. Olson, Elaine A. Cassidy, Thomas A. Griffin, Linda Wagner-Weiner, Jennifer E. Weiss, Larry B. Vogler, Kelly A. Rouster-Stevens, Timothy Beukelman, Randy Q. Cron, Daniel Kietz, Kenneth Schikler, Jay Mehta, Tracy V. Ting, James W. Verbsky, B. Anne Eberhard, Bin Huang, Chen Chen, Edward H. Giannini. Authors involved in the clinical trial are listed in the Acknowledgement and affiliations in the online supplementary. (The position of this study group in the author list is shown in the main document)

      • Contributors JYL performed the mass cytometry (cytometry by time of flight

        (CyTOF)), sorting and NanoString experiments and analysis. PC and SLP helped with the CyTOF and NanoString runs. FA, CC and SNH helped with mRNA processing and NanoString. LP helped write the R scripts for the CyTOF analysis. LL helped with the CyToF. LTB helped with sample processing. DL, JGY, ESCL, TA and PRSCG helped with patient recruitment. SA was the lead principal investigator.

      • Funding Grant support from the National Medical Research Council (NMRC) (NMRC/STaR/020/2013, NMRC/MOHIAFCAT2/2/08, MOHIAFCAT2/0001/2014, NMRC MOHIAFCAT1-6003, centre grants, TCR15Jun006, NMRC/CIRG/1460/2016, MH 095:003\016-0002), Duke-NUS, A*STAR-BMRC (IAF311020), BMRC (SPF2014/005) is gratefully acknowledged.

      • Competing interests None declared.

      • Patient and public involvement statement This research was done without patient involvement. Patients were not invited to comment on the study design and were not consulted to develop patient relevant outcomes or interpret the results. Patients were not invited to contribute to the writing or editing of this document for readability or accuracy.

      • Patient consent for publication Not required.

      • Ethics approval All samples were collected upon informed consent. All experiments were conducted according to the principles expressed in the Declaration of Helsinki, and institutional review board approved by the Sanford-Burnham or KK Women’s and Children’s Hospital IRB Committee.

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

      • Data availability statement Data are available upon reasonable request.