Faculty Collaboration Database

Immunome perturbation is present in patients with juvenile idiopathic arthritis who are in remission and will relapse upon anti-TNFα withdrawal. Ann Rheum Dis 2019 Dec;78(12):1712-1721

Date

09/22/2019

Pubmed ID

31540934

Pubmed Central ID

PMC6900250

DOI

10.1136/annrheumdis-2019-216059

Scopus ID

2-s2.0-85072566229 (requires institutional sign-in at Scopus site)   15 Citations

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with JIA (n=20) who displayed continuous clinical inactivity for at least 6 months with anti-TNFα and were subsequently withdrawn from therapy for 8 months, and scored as relapse or remission.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.

Author List

Leong JY, Chen P, Yeo JG, Ally F, Chua C, Nur Hazirah S, Poh SL, Pan L, Lai L, Lee ESC, Bathi LDT, Arkachaisri T, Lovell D, Albani S, Pediatric Rheumatology Collaborative Study Group

Author

Calvin B. Williams MD, PhD Chief, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Arthritis, Juvenile
Biological Products
CD4-Positive T-Lymphocytes
Child
Female
Follow-Up Studies
Humans
Immunity, Cellular
Male
Recurrence
Remission Induction
Tumor Necrosis Factor-alpha
Withholding Treatment