Circulating PCSK9 relates to aggravated disease activity, Th17/Treg imbalance, and predicts treatment outcome of conventional synthetic DMARDs in rheumatoid arthritis patients

Abstract

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates inflammatory response and CD4⁺ T cell differentiation in autoimmune diseases, while its clinical role in rheumatoid arthritis (RA) lacks sufficient evidence. Subsequently, this study intended to explore the vertical change of PCSK9, and its linkage with T helper (Th) cells, regulatory T (Treg) cells, clinical features, and treatment outcomes in RA patients.

Methods: This multi-center, prospective, cohort study determined serum PCSK9 in 89 RA patients who received conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and 50 healthy controls (HCs) after recruitment by enzyme-linked immunosorbent assay. For RA patients, serum PCSK9 was also determined at 6th week, 12th week, and 24th week; meanwhile, Th1, Th2, Th17, and Treg cells at baseline were determined through flow cytometry.

Results: PCSK9 was increased in RA patients compared to HCs (median: 209.2 versus 122.0 ng/mL, P < 0.001). In RA patients, PCSK9 positively correlated with Th17 cells (P = 0.023) and Th17/Treg ratio (P = 0.018), but did not link with Th1 cells, Th2 cells, Th1/Th2 ratio, or Treg cells. Meanwhile, PCSK9 was not associated with any demographics and medication histories, while it positively correlated with C-reactive protein (P = 0.010), disease activity score in 28 joints (P = 0.009), physician's global assessment (P = 0.015), and clinical disease activity index (P = 0.040). Importantly, PCSK9 gradually reduced from baseline to 24th week; its decrement related to higher possibility of treatment response (P = 0.002), low disease activity (P = 0.001), and remission of csDMARDs (P = 0.012).

Conclusion: Circulating PCSK9 shows the potency as a biomarker for disease management and treatment outcome prediction of csDMARDs in RA.

Keywords: CD4+ T cell; Clinical features; PCSK9; Rheumatoid arthritis; Treatment outcomes.