Background/Purpose: Childhood-onset Sjögren Disease (cSjD) is a rare, poorly understood autoimmune rheumatic disease with onset before 18 years. Differences in clinical presentation compared to adults/lack of evidence-based therapies, warrant research into cSjD pathogenesis. We aimed to characterize the peripheral blood immunological landscape of cSjD.

Methods: A pilot cross-sectional study of the peripheral blood immune phenotype was conducted using conventional flow cytometry methodology/analysis of children and adolescents with cSjD (N=10; mean age (range)=18 (16-21) years; all female; mean age (range) at diagnosis=14 (12-17) years; off steroids/biologic treatment naïve) compared to age/sex-matched healthy controls (cHCs; N=10; mean age (range)=18 (15-25) years; all female). The identified phenotype was further explored using 30-feature spectral flow cytometry in a larger cohort of cSjD (mean age (range)=21 (17-30) years; all female, mean age (range) at diagnosis=15 (7-17) years) and cHCs (mean age (range)=19 (15-27) years; all female) (N=19/group) using unsupervised dimensionality reduction (UMAP)/clustering (FlowSOM) analysis. Serum cytokines were assessed by Cytometric Bead Array/Luminex.

Results: CD4+ T-cell and B-cell populations were significantly dysregulated in young people with cSjD compared with matched cHCs using conventional flow cytometry analysis, characterized by elevated CD4+ effector memory (EM, p=0.01), terminally differentiated CD4+EMRA (p=0.0002) naïve (p=0.01) and activated (p=0.008) B-cell populations and reduced CD4+ central memory T-cells (p=< 0.0001) and memory B-cells (p=< 0.02). The wider immune landscape of cSjD vs CHCs was further explored using unsupervised high-parameter spectral flow cytometry. Multiple T-cell and B-cell clusters were differentially regulated in cSjD patients compared to cHCs. Notably, two CD45RA- memory T-cells clusters expressed high levels of PD-1, CXCR3 and ICOS, suggesting an activated T-follicular helper-1 phenotype; while other clusters had elevated PD-1 and/or ICOS. This pro-inflammatory and activated T-cell phenotype was supported by increased production of IL-6 by CD4+ T-cells (p=0.04) and increased serum IL-6 levels (p=0.02) in young people with cSjD vs cHCs. One B-cell cluster was significantly upregulated in cSjD (p=0.0001), with high levels of CD24 and CD38, suggesting a transitional B-cell phenotype. This cluster was significantly positively correlated with activated T cell clusters. Finally, cytokines associated with B-cell activation, IL-10 (p=0.01) and APRIL (p=0.0007), and immune cell trafficking, CCL8 (p=0.03), were also increased in cSjD, suggesting immune dysregulation and increased chemotactic activity.

Conclusion: While adult-onset SjD is characterized by peripheral CD4+ T-cell lymphopenia, we detected an opposite trend towards significant expansion of CD4+ T-cell subset frequencies in cSjD. This could have significant therapeutic implications, suggesting that cSjD may recapitulate the early phase of the corresponding adult disease phenotype, when treatments with T-cell targeted (such as abatacept, low dose IL2) or broader (such as leflunomide or cyclosporine A) effects could be beneficial.  

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/childhood-onset-sjogren-disease-has-an-altered-peripheral-blood-immune-landscape-compared-to-adult-onset-disease-characterized-by-activated-cd4-t-cells-which-could-drive-b-cell-dysregulation/