Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
Early diagnosis of rheumatoid arthritis (RA) improves outcomes but is challenging, particularly amongst anti-citrullinated peptide auto-antibody (ACPA) negative individuals. Previously we identified an IL-6 mediated CD4+T cell transcriptional signature, enriched for signal transduction and activation of transcription-3 (STAT3) target genes, which had discriminatory value for this purpose. In the present work we sought a more readily applicable diagnostic assay, and insight into mechanisms of disease induction.
Amongst early arthritis patients and controls naïve to immunomodulatory treatment, constitutive and IL-6-induced expression of phosphorylated STAT1 and 3 (pSTAT1/3) were determined in circulating lymphocytes using flow cytometry. Contemporaneous serum cytokine levels were measured using a validated, highly sensitive immuno-assay, and normalised CD4+T cell gene expression of the previously described STAT3 target gene-enriched signature was determined using microarray.
In 187 early arthritis patients, constitutive pSTAT3 correlated with serum IL-6 levels maximally in CD4+ T cells, compared with other circulating leukocyte subsets. Increased constitutive pSTAT3, but not pSTAT1, was observed in circulating CD4+ T cells of early ACPA negative RA patients compared with disease controls. Amongst patients presenting with undifferentiated arthritis (UA) the ratio of constitutive pSTAT3:pSTAT1 in CD4+ T cells could be incorporated into an algorithm for predicting progression to classifiable RA with high accuracy (area under ROC curve = 0.91; p<0.001). The comparable utility of the previously described CD4+T cell gene signature as a discriminatory tool, and the accuracy of pSTAT3:pSTAT1 as a surrogate for target gene expression, are the subject of on-going analyses.
Our findings support a particular role for IL-6-driven CD4+ T cell activation via STAT3 during the induction of RA, which may be of particular importance in the pathogenesis of ACPA-negative disease. CD4+ pSTAT measurements show promise as biomarkers of progression to RA in sero-negative UA.
A. E. Anderson,
A. G. Pratt,
J. D. Isaacs,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phospho-stat13-and-gene-expression-measurement-in-circulating-cd4-t-cells-as-diagnostic-tools-in-early-autoantibody-negative-rheumatoid-arthritis/