Insights into knee post-traumatic osteoarthritis pathophysiology from the relationship of serum biomarkers to radiographic features in the ADVANCE cohort.

INTRODUCTION: Post-traumatic osteoarthritis (PTOA) is a complex condition with multiple pathological processes at play. Molecular biomarkers can enable a better understanding of these processes, thus enhancing case endotyping, phenotyping, personalised care and drug discovery. The longitudinal ArmeD SerVices TrAuma and RehabilitatioN OutComE (ADVANCE) study offers the opportunity to develop insights into PTOA pathophysiology using a panel of extra-cellular matrix turnover, inflammatory and metabolic biomarkers and their cross-sectional (associative) and longitudinal (predictive) relationship to features of radiographic PTOA in a cohort of young, male, severely injured servicepersonnel. METHODS: Using serum and radiographic data gathered in the baseline (8-years) and first follow-up visit (11-years) post-injury of ADVANCE (n = 1145), two analyses were undertaken. Firstly, cross-sectional univariate analysis between serum COMP, CTX-II, PIIANP, IL-1b, IL-17a, TNF-a, leptin and adiponectin and radiographic features (joint space narrowing (JSN), osteophytes and sclerosis), followed by the longitudinal prediction of new or progression of these three radiographic features using LASSO to select predictors. The area under a ROC curve (AUROC) was computed. RESULTS: Complete radiographic and serum case data in n = 872 male British servicemen, aged 34.5 (5.5) at baseline and 38.3 (5.4) at follow-up were analysed. Those with JSN had significantly higher concentrations of leptin (FDR-corrected q-value, q = 0.04). COMP had an AUROC of 0.604 (0.543,0.664) for new cases of JSN, COMP, IL-1β and leptin had an AUROC 0.586 (0.524,0.646) for new osteophytes, and TNF-α, IL-1β and adiponectin had an AUROC 0.590 (0.520,0.659) for new sclerosis. CONCLUSION: This large, unique study suggests different pathological processes underpinning each radiographic feature of PTOA, including predominant unbalanced ECM-catabolism and inflammation contributing to JSN, ECM-catabolism and increased inflammation contributing to osteophyte development and an inflammation-predominant process contributing to subchondral sclerosis.