Abstract
ObjectiveSeropositive arthralgia patients (SAP) are at high risk of developing rheumatoid arthritis (RA). This prospective study aimed to determine whether altered peripheral regulatory T-cells (Tregs) and defined subsets, besides a broadened anti-citrullinated protein antibody (ACPA) response, may qualify as biomarkers for RA development in SAP.MethodsThirty-four consecutive SAP were prospectively assessed every 6 months for minimally 2 years. At inclusion, peripheral Treg (CD4+CD25+FoxP3+) numbers and subsets, defined as CD45RA+FoxP3low naive Tregs (Fr I), CD45RA-FoxP3high activated Tregs (Fr II) and CD45RA-FoxP3low non-Tregs (Fr III), were compared to age- and sex-matched healthy controls (HC, n = 16) and treatment-naive RA patients (n = 12). SAP that developed RA were compared to non-switchers and analyzed for Treg numbers and Treg subsets at inclusion. Also, Treg numbers and subsets were compared in switched SAP before and at diagnosis. To assess the ACPA repertoire, IgG and IgA reactivity was measured against citrullinated peptides from fibrinogen, α-enolase and vimentin.ResultsTreg numbers were similar between HC, SAP and RA patients. Although the bonafide Treg subsets Fr I and Fr II were comparable between groups, Fr III was increased in SAP compared to HC (p = 0.01). Fourteen (41%) SAP developed RA during follow-up. Their Treg numbers and subsets were comparable to non-switched SAP. At RA diagnosis, Treg numbers in switched SAP were similar to 6 months before. Switched SAP displayed a more diverse IgG ACPA repertoire compared to non-switched SAP (p = 0.046) and showed more IgA reactivity than non-switched SAP reaching significance for Fib1 only (p = 0.047).ConclusionNumbers of Total Treg and bonafide Treg subsets are not indicative for RA development in SAP, opposed to the ACPA repertoire.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the joints and by a breakdown of self-tolerance [1]
The bonafide Treg subsets Fr I and Fr II were comparable between groups, Fr III was increased in Seropositive arthralgia patients (SAP)
The frequency of CD4+CD25+forkhead box protein 3 (FoxP3)+ T-cells among Peripheral blood mononuclear cells (PBMCs) in healthy controls (HC), SAP at inclusion and RA was assessed by flow cytometry (Fig 1A)
Summary
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the joints and by a breakdown of self-tolerance [1] This breakdown is reflected by the induction of autoantibodies, such as rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-citrullinated protein antibodies (ACPA) directed against self-proteins which are found in the majority of RA patients [2]. These autoantibodies can be detected in serum years before disease development [3,4]. Fr III cells, have no suppressive function, but are able to secrete cytokines such as IL-2, IFN-γ and IL-17
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