Systemic and local autoantibody responses to extracellular matrix proteins define inflammatory phenotypes across arthropathies

Abstract Objectives Autoantibodies targeting extracellular matrix proteins are emerging as critical contributors to arthritis pathogenesis, yet their presence across different arthropathies remains incompletely characterized. This study investigated systemic and local expression of proteoglycan 4 (PRG4) and cartilage oligomeric matrix protein (COMP), alongside their corresponding autoantibodies, in healthy controls and patients with osteoarthritis (OA), rheumatoid arthritis (RA), or juvenile idiopathic arthritis (JIA). Methods Serum and synovial fluid samples were analyzed by ELISA from control subjects, OA, RA, and JIA patients. Results Serum PRG4 levels were significantly decreased in RA compared to controls and OA, while JIA patients showed elevated levels. Serum COMP was significantly elevated in OA and JIA compared to controls and RA. In synovial fluid, OA showed decreased PRG4 compared to all other groups, while COMP levels were highest in OA and controls. Anti-PRG4 autoantibodies were significantly elevated in all disease groups compared to controls in serum, with RA and JIA also showing increased elevation in synovial fluid. Anti-COMP autoantibodies were significantly increased in RA and JIA serum and elevated in all disease groups in synovial fluid compared to controls. Notably, a positive correlation between PRG4 protein and anti-PRG4 antibodies was observed specifically in OA synovial fluid, suggesting local antigen-driven immune responses. Conclusions These findings demonstrate that autoantibodies against PRG4 and COMP are present across arthropathies with distinct patterns reflecting different pathogenic mechanisms. The detection of these autoantibodies provides mechanistic insights into disease progression and potential biomarkers for identifying differential pathway activation/inflammatory subgroups within arthropathies.