Clinical and molecular links between chronic systemic inflammation and structural damage in axial spondyloarthritis

Structural damage in axial spondyloarthritis (axSpA) is closely linked to chronic inflammation, yet the underlying mechanisms remain incompletely understood. For that reason, we investigated the relationship between persistent systemic inflammation and radiographic damage in axSpA and characterized the associated molecular and cellular pathways. A retrospective registry of 238 axSpA patients was stratified by C-reactive protein (CRP) trajectory over the last 5 years into non-persistent, intermediate, and persistent inflammation groups. Radiographic damage, serum bone metabolism markers, and proteomic profiles (Olink 184-protein panel) were assessed. In vitro assays in SaOS-2 osteoblast-like cells evaluated functional responses to CDCP1, CRP, and patient serum. Persistent inflammation was observed in 25.2% of patients and was independently associated with greater radiographic damage, including higher total and lumbar mSASSS scores and syndesmophyte counts. Proteomic analysis revealed a distinct inflammatory signature in persistently inflamed patients, marked by elevated levels of MMP9, IL-6, CDCP1, and neutrophil-related proteins. CDCP1 strongly correlated with radiographic damage and bone turnover markers. Functional assays showed that CDCP1 and CRP modulate osteoblast gene expression, promoting osteogenic and inflammatory pathways in a dose-dependent manner. Moreover, serum from persistently inflamed axSpA patients induced osteogenic remodeling in vitro. Persistent systemic inflammation in axSpA is a key independent driver of structural damage and is linked to a distinct proteomic and functional signature involving neutrophil activation and bone remodeling. CDCP1 may serve as a potential biomarker and mediator of inflammation-driven osteoproliferation in axSpA.