Association of plasma sPD-1 and sPD-L1 with disease status and future relapse in AQP4-IgG (+) NMOSD

Objective: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated disorder with aquaporin 4-immunoglobulin G (AQP4-IgG) in most settings. Soluble programmed death-1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) play key roles in immunomodulation. We aim to assess the association of sPD-1 and sPD-L1 with cytokines and their clinical significance in AQP4-IgG (+) NMOSD. Method: We measured plasma sPD-1, sPD-L1, and 10 cytokines levels of 66 AQP4-IgG (+) NMOSD patients, including 40 patients in attack (attack-NMOSD) and 26 patients in remission (remission-NMOSD) phases, and 28 healthy controls through ultrasensitive Simoa and SP-X platform, respectively. We also performed >2 years (median) of follow-up after testing and analyzed the relationship between the detection index and current and future clinical parameters. Result: Plasma sPD-1 level discriminated attack-NMOSD from remission-NMOSD (AUC = 0.692, p = 0.009). sPD-1 and sPD-L1 levels positively correlated with IL-6 (r(sPD-1) = 0.313; r(sPD-L1) = 0.508), IFN-gamma (r(sPD-1) = 0.331; r(sPD-L1) = 0.456), and TNF-alpha (r(sPD-1) = 0.451; r(sPD-L1) = 0.531) expression, as well as clinical indicators, including the EDSS score (r(sPD-1) = 0.331; r(sPD-L1) = 0.402), number of attacks (r(sPD-1) = 0.431) and segments of spinal cord involvement (r(sPD-1) = 0.462; r(sPD-L1) = 0.508). The risk of relapse within 2 years after sampling was associated with higher sPD-1/sPD-L1 ratio in attack-NMOSD (p = 0.022; Exp(B) = 1.589). Interpretation: Plasma sPD-1 and sPD-L1 levels reflected current disease severity and activity, and predicted future relapses in AQP4-IgG (+) NMOSD, suggesting that they hold the potential to guide timely and targeted treatment.