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An immunome perturbation is present in juvenile idiopathic arthritis patients who are in remission and will relapse upon anti-TNFα withdrawal

J. Leong,Phyllis Chen,J. G. Yeo,F. Ally,C. Chua,S. Hazirah,S. Poh,Lu Pan,L. Lai,Elene Seck Choon Lee,L. Bathi,T. Arkachaisri,D. Lovell,S. Albani

Published 2019 in bioRxiv

ABSTRACT

Objectives Biologics treatment with anti-TNFα is efficacious in juvenile idiopathic arthritic (JIA) patients. Despite displaying clinical inactivity during treatment, many patients will flare upon 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 (CyToF) of JIA patients (n=20) who displayed continuous clinical inactivity for at least 6 months with anti-TNFα, and were subsequently withdrawn from therapy for 8 months, and scored as relapse or remission.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 continued 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 (a) TCR activation, (b) apoptosis, (c) TNFα, (d) NF-kB and (e) MAPK signalling. Conclusions A unique discriminatory immunomic and transcriptomic signature is associated with relapse patients and may explain how relapse occurs.

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