Association of Soluble Immune Checkpoint Molecules PD1 and 4-1BB With CTLA-4Ig Treatment Response in Early Rheumatoid Arthritis.

Objective: To investigate whether soluble immune checkpoint molecules in blood are associated with the treatment response to disease-modifying antirheumatic drugs in early rheumatoid arthritis (eRA).

Methods: This study included 328 Swedish treatment-naïve patients with eRA from the Nordic Rheumatic Diseases Strategy Trials and Registries (NORD-STAR) study. Patients were randomized into four treatment groups: methotrexate (MTX) combined with CTLA-4Ig (n = 90), anti-tumor necrosis factor (n = 83), anti-interleukin-6 receptor (n = 76), or prednisolone (n = 79). The primary outcome was remission, defined by Clinical Disease Activity Index (CDAI) ≤2.8, assessed at 24 and 48 weeks. Plasma levels of soluble programmed cell death-1 (sPD1) and soluble 4-1BB (s4-1BB) were measured by enzyme-linked immunosorbent assay at baseline and at weeks 24 and 48 after treatment initiation.

Results: High baseline levels of sPD1 and s4-1BB were both associated with CDAI remission at 24 weeks (odds ratio 1.31, 95% confidence interval [CI] 1.04-1.66 and odds ratio 1.50, 95% CI 1.07-2.11, respectively) in patients treated with CTLA-4Ig with MTX, but not in any other treatment groups. Furthermore, baseline levels of sPD1 or s4-1BB together with proportions of PD1⁺ T follicular helper (TFh) cells predicted treatment response to CTLA-4Ig with MTX after 48 weeks, achieving 90% and 100% positive predictive value, respectively.

Conclusion: High plasma levels of sPD1 and s4-1BB are associated with good response to CTLA-4Ig with MTX therapy in patients with eRA. A combination of sPD1 or 4-1BB levels and the proportions of PD1⁺ TFh cells in blood at baseline has potential for predicting remission after CTLA-4Ig treatment.