Association Between Inflammatory Cytokines and Immune-Checkpoint Molecule in Rheumatoid Arthritis

Background: Rheumatoid arthritis (RA) is a heterogeneous inflammatory disease. Both anti-citrullinated peptide antibodies (ACPA) and inflammatory cytokines play an important role in the development of RA. The aim of this study was to investigate the association between inflammatory cytokines and co-inhibitory checkpoint molecules in patients with RA.MethodsOne hundred and thirty-two Japanese patients with established RA were enrolled. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α) were determined by ELISA. Patients were stratified into two groups based on ACPA titers: low-medium ACPA (ACPA <200 U/mL) and high ACPA (ACPA ≥200 U/mL). Serum levels of cytokines or co-inhibitory checkpoint molecules were compared according to the status of ACPA titers and joint progression stage.ResultsBaseline serum levels of TNF-α and IL-6 were significantly elevated in RA patients; however, the two cytokines showed no correlation with each other. Serum levels of IL-6 or TNF-α showed a significant correlation with DAS28-CRP, independent of ACPA status. Although serum levels of soluble T-cell immunoglobulin and mucin-domain containing-3 (sTIM-3) were elevated in RA patients, significant correlation of sTIM-3 with IL-6 or TNF-α was only observed in RA patients with low-medium levels of ACPA titers (<200 U/mL). Serum levels of IL-6 and TNF-α were significantly correlated with elevated levels of galectin-9 (Gal-9) independent of ACPA status. Whereas, a significant correlation between IL-6 and Gal-9 was observed only in RA patients without advanced joint damage (Stage I). Conversely, significant correlation between TNF-α and Gal-9 was observed only in RA patients with advanced joint damage (Stage II–IV).ConclusionsRA patients may be differentiated based on the interplay between serum cytokines and co-inhibitory molecules. RA patients with minimal joint damage (Stage I) appear to show positive correlation between Gal-9 and IL-6. Conversely, RA patients with advanced joint damage (Stage II–IV) appear to show positive correlation between Gal-9 and TNF-α. Serum levels of cytokines and immune-checkpoint molecules may be useful markers for predicting the immune phenotype and further personalized treatment of RA.