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IL-6-driven STAT signalling in circulating CD4+ lymphocytes is a marker for early anti-citrullinated peptide antibody-negative rheumatoid arthritis

Lookup NU author(s): Dr Amy AndersonORCiD, Dr Arthur PrattORCiD, Dr John Doran, Christine Routledge, Ben Hargreaves, Dr Phillip Brown, Professor John IsaacsORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


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.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

Publication metadata

Author(s): Anderson AE, Pratt AG, Sedhom MA, Doran JP, Routledge C, Hargreaves B, Brown PB, LeCao KA, Isaacs JD, Thomas R

Publication type: Article

Publication status: Published

Journal: Annals of the Rheumatic Diseases

Year: 2016

Volume: 75

Pages: 466-473

Print publication date: 01/02/2016

Online publication date: 03/02/2015

Acceptance date: 15/12/2014

Date deposited: 02/11/2015

ISSN (print): 0003-4967

ISSN (electronic): 1468-2060

Publisher: BMJ Publishing Group


DOI: 10.1136/annrheumdis-2014-205850

PubMed id: 25649145


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Funder referenceFunder name
Academy of Medical Sciences
NIHR Newcastle Biomedical Research Centre at Newcastle upon Tyne Hospitals Foundation Trust & Newcastle University