title: Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis.
abstract: OBJECTIVE
  Programmed death-1 (PD-1) is an immunoregulatory molecule functioning by down-regulating immune responses. PD-1 is present on follicular helper T cells (TFH) and is important in the formation of plasma cells. PD-1 exists in a bioactive soluble form (sPD-1) and is thought to be implicated in disease activity in chronic rheumatoid arthritis (RA).
  
  
  METHODS
  We measured sPD-1 at baseline and 9 months after treatment initiation in plasma from early RA patients (n = 34). We tested for correlations with the Disease Activity Score using 28 joint counts (DAS28), the Health Assessment Questionnaire (HAQ) score, immunoglobulin M rheumatoid factor (IgM-RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, C-reactive protein (CRP), interleukin-21 (IL-21), and total Sharp score (TSS). We also measured sPD-1 in plasma from healthy volunteers (HV) (n = 20) and in plasma and synovial fluid (SF) from patients with chronic RA (> 8 years of disease, n = 30). We further investigated the cellular expression of PD-1 and its ligand PD-L1.
  
  
  RESULTS
  sPD-1 concentrations in early [median 0.421 ng/mL, interquartile range (IQR) 0.04-2.560 ng/mL] and chronic (median 0.239 ng/mL, IQR 0.184-0.584 ng/mL) RA were increased compared with HV (median 0.04 ng/mL, IQR 0.04-0.04 ng/mL) (all p < 0.005). In early RA the change in sPD-1 was associated with DAS28 (r = 0.363, p < 0.05) and HAQ score (r = 0.554, p < 0.05) and inversely with TSS at 3-5 years (r = -0.468, p < 0.05). sPD-1 concentration correlated with IgM-RF, anti-CCP antibodies, and IL-21 (all p < 0.05). PD-1 was primarily expressed by synovial memory T cells whereas PD-L1 was mainly expressed by synovial monocytes.
  
  
  CONCLUSIONS
  The significantly elevated plasma levels of sPD-1 in early RA, the association with core disease parameters, and the inverse correlation with TSS suggest that sPD-1 is an important mediator in inflammatory and radiographic disease progression.
authors.affiliation: Institute of Biomedicine, University of Aarhus , Aarhus , Denmark.
authors.forename: S R
authors.initials: SR
authors.lastname: Greisen
authors.forename: T K
authors.initials: TK
authors.lastname: Rasmussen
authors.forename: K
authors.initials: K
authors.lastname: Stengaard-Pedersen
authors.forename: M L
authors.initials: ML
authors.lastname: Hetland
authors.forename: K
authors.initials: K
authors.lastname: Hørslev-Petersen
authors.forename: M
authors.initials: M
authors.lastname: Hvid
authors.forename: B
authors.initials: B
authors.lastname: Deleuran
mesh_terms: D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000000981:diagnostic imaging* / Q000188:drug therapy; D001623:Betamethasone / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016572:Cyclosporine / Q000627:therapeutic use; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007378:Interleukins / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000097:blood*; D011859:Radiography; D012217:Rheumatoid Factor / Q000097:blood; D012720:Severity of Illness Index; D000098546:Interleukin-21
chemical_list: D000888:Antibodies, Anti-Idiotypic; D015415:Biomarkers; D007378:Interleukins; C105992:PDCD1 protein, human; D010456:Peptides, Cyclic; D061026:Programmed Cell Death 1 Receptor; C487763:cyclic citrullinated peptide; D016572:Cyclosporine; D012217:Rheumatoid Factor; D001623:Betamethasone; D000098546:Interleukin-21; D008727:Methotrexate