Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis

Abstract

Objectives: Programmed death-1 (PD-1) is an immunoregulatory molecule functioning by down-regulating immune responses. PD-1 is present on follicular helper T cells (T_FH) 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).

Method: 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.

Acknowledgements

This work was funded by unrestricted grants from Novo Nordisk, Leo Pharma, Merck, Roche, Novartis, and the Danish Association Against Rheumatism, and also by the Danish Graduate Programme for In Vivo Pharmacology and the Institute of Clinical Medicine at the University of Aarhus.