Metabolomics Signature for Non-Responders to Total Joint Replacement Surgery in Primary Osteoarthritis Patients: The Newfoundland Osteoarthritis Study.

Although total joint replacement (TJR) surgery is considered as the most effective treatment for advanced osteoarthritis (OA) patients, up to one-third of patients reported unfavorable long-term post-operative pain outcomes. We aimed to identify metabolic biomarkers to predict non-responders to TJR using a metabolomics approach. TJR patients were recruited and followed-up at least 1-year post-surgery; TJR outcomes were assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function subscales. Targeted metabolomic profiling was performed on plasma samples collected pre-surgery and pairwise metabolite ratios, as proxies for enzymatic reactions, were calculated. Association tests were performed between each metabolite ratio and non-responders. The metabolome-wide significance was defined as p < 2 × 10-5 . A total of 461 TJR patients due to primary OA were included in the analysis. Fifteen percent of patients were classified as pain non-responders; 16% were classified as function non-responders. Lower baseline WOMAC pain and function scores were significantly associated with pain and function non-responders, respectively (both p < 0.03). Two metabolite ratios were significantly associated with pain non-responders; acetylcarnitine (C2) to phosphatidylcholine acyl-alkyl C40:1 (PC ae C40:1) was five times higher in pain non-responders whereas phosphatidylcholine diacyl C36:4 (PC aa C36:4) to isoleucine was twenty one times lower in pain non-responders than responders (all p ≤ 1.93 × 10-5 ). One metabolite ratio, glutamine to isoleucine, was significantly lower in function non-responders than responders (eight times lower; p = 1.08 × 10-5 ). Three metabolite ratios (C2 to PC ae C40:1, PC aa C36:4, and glutamine to isoleucine) related to inflammation and muscle breakdown could be considered as novel plasma markers for predicting non-responders to TJR and warrant further investigation.