Objectives. IL-6-mediated signal transduction and activator of transcription 3 (STAT3) and STAT1 signalling was investigated in circulating lymphocytes of early arthritis patients, seeking insight into rheumatoid arthritis (RA) pathogenesis, and biomarkers of potential clinical utility.
Methods. Amongst participating patients and controls, constitutive and IL-6-induced expression of phosphorylated Stat1 (pSTAT1) and pSTAT3 were determined in T and B cells using Phosflow cytometric analysis. Contemporaneous levels of serum cytokines were measured by immunoassay. Induced gene expression was measured in cultured CD4+ T cells by quantitative real-time PCR.
Results. Amongst circulating lymphocytes of 187 early arthritis patients, constitutive pSTAT3 correlated with serum IL-6 levels maximally in CD4+ T cells. Increased constitutive pSTAT3, but not pSTAT1, was observed in circulating CD4+ T-cells of early ACPA-negative RA patients compared with disease controls, and these levels decreased alongside markers of disease activity with IL-6R targeted treatment. Amongst patients presenting with seronegative undifferentiated arthritis (UA) the ratio of constitutive pSTAT3:pSTAT1 in CD4+ T cells could be incorporated into an algorithm for accurately predicting progression to classifiable RA during a median 15 month follow-up period (area under ROC curve = 0.90; p<0.001).
Conclusions. Our findings support a particular role for IL-6-driven CD4 + T cell activation via STAT3 during the induction of RA, particularly as a feature of ACPA-negative disease. CD4+ T-cell pSTAT measurements show promise as biomarkers of progression to RA in sero-negative UA.