PT  - JOURNAL ARTICLE
AU  - Amy E Anderson
AU  - Arthur G Pratt
AU  - Mamdouh A K Sedhom
AU  - John Paul Doran
AU  - Christine Routledge
AU  - Ben Hargreaves
AU  - Philip M Brown
AU  - Kim-Anh Lê Cao
AU  - John D Isaacs
AU  - Ranjeny Thomas
TI  - IL-6-driven STAT signalling in circulating CD4+ lymphocytes is a marker for early anticitrullinated peptide antibody-negative rheumatoid arthritis
AID  - 10.1136/annrheumdis-2014-205850
DP  - 2016 Feb 01
TA  - Annals of the Rheumatic Diseases
PG  - 466--473
VI  - 75
IP  - 2
4099  - http://ard.bmj.com/content/75/2/466.short
4100  - http://ard.bmj.com/content/75/2/466.full
SO  - Ann Rheum Dis2016 Feb 01; 75
AB  - Objectives A previously identified signal transduction and activator of transcription-3 (STAT3) target-enriched gene signature in circulating CD4+ T cells of patients with early rheumatoid arthritis (RA) was prominent in autoantibody-negative individuals. Here, interleukin (IL)-6-mediated STAT signalling was investigated in circulating lymphocytes of an independent early arthritis patient cohort, seeking further insight into RA pathogenesis and biomarkers of potential clinical utility.Methods Constitutive and IL-6-induced expression of phosphorylated STAT1 (pSTAT1) and pSTAT3 was determined in T and B cells using Phosflow cytometric analysis in patients with RA and controls. 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 Among circulating lymphocytes of 187 patients with early arthritis, 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 patients with early anticitrullinated peptide autoantibody (ACPA)-negative RA compared with disease controls, and these levels decreased alongside markers of disease activity with IL-6R-targeted treatment. Among patients presenting with seronegative undifferentiated arthritis (UA) the ratio of constitutive pSTAT3:pSTAT1 in CD4+ T cells contributed substantially to an algorithm for predicting progression to classifiable RA during a median of 20 months follow-up (area under receiver operator characteristic curve=0.84; 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 UA–RA progression and now require independent validation.