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

Abstract

ObjectivesBiologics 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.MethodsWe 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with JIA (n=20) who displayed continuous clinical inactivity for at least 6 months with anti-TNFα and were subsequently withdrawn from therapy for 8 months, and scored as relapse or remission.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.ResultsAn 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.ConclusionsA unique discriminatory immunomic and transcriptomic signature is associated with relapse patients and may explain how relapse occurs.

The Multi-Omics Architecture of Juvenile Idiopathic Arthritis

“…CD27, CD276, CTLA4, IL2RG, and SLAMF7 are significantly upregulated in patients with sJIA-related lung diseases, suggesting the activation of T cells [ 112 ]. By the transcriptome analysis of 579 immune genes of T cells, UBE2L3 , IL-6 , STAT4 , TYK2 , TNFAIP3, and PTPN2 were significantly dysregulated in the relapse and remission of JIA cases [ 113 ]. Upregulation of HLA class II and another less-appreciated marker of T-cell activation, CD86, was found in the transcriptome profiling of 92% of JIA samples tested for DNA methylation [ 114 ].…”

Biomarkers of Response to Biologic Therapy in Juvenile Idiopathic Arthritis

“…The difference in the anti-DEK levels between the groups was significant based on samples taken after patients flared, whilst anti-DEK levels at the time of discontinuation could not predict the outcome ( Mor-Vaknin et al, 2018 ). Finally, an increased population frequency of an inflammatory CD4 memory subset (CD3 + CD4 + CD45RA − TNFα + ) predicted relapse at 8 months after discontinuation of biologic therapy (AUC = 0.939) in polyarticular JIA patients with inactive disease prior to treatment cessation ( Leong et al, 2019 ).…”

Progress and applications of mass cytometry in sketching immune landscapes

“…Many studies have used CyTOF to examine the pathogenesis of autoimmune diseases (Table 4). 18,36,[106][107][108][109][110][111] Several researchers focused on the immunome perturbations in patients with rheumatoid arthritis, a chronic autoimmune, inflammatory disease depicted with synovitis in small-and medium-sized joints, 18,[106][107][108][109] exploring both the peripheral blood 18,107 and synovium tissue samples. 106,108 In one study, 106 the investigators examined synovitis of patients with rheumatoid arthritis through a 36-plex CyTOF panel specific to activated T cells.…”

“…113 Another study, with the aid of CyTOF, interrogated the circulatory reservoir of CD4 + subsets in juvenile idiopathic arthritis patients undergoing TNFalpha therapy withdrawal and found putative subsets prior to withdrawal that discriminated relapse from remission. 111 Researchers have also provided comprehensive overview of distinct immune signatures in multiple autoimmune conditions, including psoriasis, [114][115][116] neuroinflammation, 117 and multiple sclerosis. 118 Together, these results provided a strong foundation for CyTOF studies with increased dimensionality to characterize central immune mediators in various autoimmune disorders.…”

“…Similarly, Slight‐Webb's groups applied CyTOF to reveal the STAT3 phosphorylation reduction after mycophenolate mofetil treatment in SLE 113 . Another study, with the aid of CyTOF, interrogated the circulatory reservoir of CD4 + subsets in juvenile idiopathic arthritis patients undergoing TNF‐alpha therapy withdrawal and found putative subsets prior to withdrawal that discriminated relapse from remission 111 . Researchers have also provided comprehensive overview of distinct immune signatures in multiple autoimmune conditions, including psoriasis, 114–116 neuroinflammation, 117 and multiple sclerosis 118 .…”