title: Regulatory CD4+ T-Cell Subsets and Anti-Citrullinated Protein Antibody Repertoire: Potential Biomarkers for Arthritis Development in Seropositive Arthralgia Patients?
abstract: OBJECTIVE
  Seropositive 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.
  
  
  METHODS
  Thirty-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.
  
  
  RESULTS
  Treg 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).
  
  
  CONCLUSIONS
  Numbers of Total Treg and bonafide Treg subsets are not indicative for RA development in SAP, opposed to the ACPA repertoire.
authors: Department of Oral and Maxillofacial Surgery, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Koen M J
authors: KM
authors: Janssen
authors: Department of Rheumatology and Clinical Immunology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Johanna
authors: J
authors: Westra
authors: Department of Rheumatology and Clinical Immunology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Paulina
authors: P
authors: Chalan
authors: Department of Rheumatology and Clinical Immunology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Annemieke M H
authors: AM
authors: Boots
authors: Center for Dentistry and Oral Hygiene, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Menke J
authors: MJ
authors: de Smit
authors: Center for Dentistry and Oral Hygiene, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.|Department of Medical Microbiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Arie Jan
authors: AJ
authors: van Winkelhoff
authors: Department of Oral and Maxillofacial Surgery, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Arjan
authors: A
authors: Vissink
authors: Department of Rheumatology and Clinical Immunology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Elisabeth
authors: E
authors: Brouwer
mesh_terms: D018771:Arthralgia / Q000097:blood*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis*; D015415:Biomarkers / Q000097:blood*; D002956:Citrulline / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016176:T-Lymphocyte Subsets; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D002956:Citrulline