Synovial infiltrating immune cell heterogeneity associated with synovitis severity and systemic disease activity in rheumatoid arthritis: a cross-sectional study

Abstract

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by persistent synovitis. The synovial inflammation observed in RA exhibits significant heterogeneity among patients.

Objective: To examine the relationship between major immune cell infiltration profiles in synovium and both local synovitis and systemic manifestations of RA.

Methods: This cross-sectional study enrolled 22 RA patients (mean disease duration: 7.1 years). Synovial biopsies were assessed using the Krenn synovitis scoring system (no/low/high-grade) and immunohistochemical pathotyping (lympho-myeloid, diffuse-myeloid, pauci-immune). Clinical parameters, including the Disease Activity Score-28 (DAS28), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and autoantibody status, were systematically analyzed.

Results: Immunohistochemical analysis identified three distinct synovial pathotypes, characterized by specific distributions of CD3⁺ T cells, CD68⁺ macrophages, CD20⁺ B cells, and CD138⁺ plasma cells. Synovitis severity, classified using the Krenn scoring system, demonstrated significant differences in synovial inflammation and stromal hyperplasia. High-grade synovitis exhibited significantly increased infiltration of CD20⁺ B cells (p = 0.025) and CD138⁺ plasma cells (p = 0.034) compared to non-inflamed tissues. Pathotype distribution analysis revealed a predominance of the pauci-immune subtype in the no-synovitis group (59.1%), whereas the lympho-myeloid subtype became progressively more prevalent with increasing synovitis severity (31.8% overall).ESR, CRP, and DAS28, were significantly correlated with synovial immune cell infiltration and synovitis severity, whereas no significant association was observed between synovitis and RA associated autoantibodies such as anti-cyclic citrullinated peptide (anti-CCP) or rheumatoid factor (RF).

Conclusion: These findings underscore the complex interactions between synovial infiltrating immune cells, synovitis severity, and systemic disease activity, providing valuable insights for the development of personalized RA management strategies. Key Points •This study characterizes synovial immune infiltrates in relation to synovitis severity and systemic disease activity in RA •High-grade synovitis, as assessed by the Krenn scoring system, is associated with increased infiltration of immune cells, such as CD20⁺ B cells and CD138⁺ plasma cells, contributing to more severe inflammation and joint destruction. •The distribution of synovial pathotypes (lympho-myeloid, diffuse-myeloid, pauci-immune) correlates with synovitis severity, providing insights into potential molecular subtypes that could influence clinical phenotypes and treatment responses in RA.

Keywords: Disease activity; Rheumatoid arthritis; Synovial immune cell; Synovitis.