Synovial Fluid Biomarkers in the Contralateral Knee Predict Patient-Reported Outcomes After Injury at Long-term Follow-up

Background: Inflammatory biomarkers in an injured knee have been shown to predict outcomes, yet the role of the subsequent systemic inflammatory response to injury remains poorly understood. Purpose: To investigate whether synovial fluid (SF) biomarkers from the contralateral uninjured knee could predict long-term patient-reported outcomes (PROs) for the operative knee in patients undergoing arthroscopic knee surgery. Study Design: Case series; Level of evidence, 4. Methods: This retrospective analysis included patients undergoing knee SF aspiration before arthroscopy with ≥8 years of follow-up. SF was aspirated from both the injured and healthy contralateral knees, and concentrations of 10 pro- and anti-inflammatory biomarkers were quantified. Patients completed visual analog scale (VAS) for pain score, Lysholm, Tegner, and Knee injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS) surveys preoperatively and at the final follow-up. Stepwise linear regression was performed to identify the most significant predictor(s) of PRO scores utilizing log-normalized contralateral biomarker concentration, age, body mass index, injury type, and Outerbridge grade as covariates. Concentrations from the contralateral knee were also compared with the injured knee to assess for correlations. Results: A total of 32 patients with a mean age 49.6 ± 12.3 years and follow-up of 10.0 ± 1.4 years were included. Elevated anti-inflammatory tissue inhibitor of metalloproteinase 1 (TIMP-1) in the contralateral knee was associated with improved VAS pain score ( P = .002) and KOOS-PS ( P < .001) at long-term follow-up. Increased levels of contralateral pro-inflammatory matrix metalloproteinase 3 ( P = .004) and regulated on activation normal T cell expressed and secreted ( P = .035) were associated with worse KOOS-PS, while elevated interleukin 1 receptor antagonist was associated with worse VAS pain ( P = .006), Lysholm ( P = .005), and Tegner ( P = .006) score at the final follow-up. Contralateral concentrations of monocyte chemotactic protein 1, macrophage inflammatory protein 1β, vascular endothelial growth factor, and TIMP-1 were correlated with levels in the operative knee but at significantly lower concentrations. Conclusion: SF biomarker levels in the contralateral uninjured knee at the time of arthroscopy were predictive of long-term outcomes for the operative knee. Increased levels of pro-inflammatory biomarkers were predictive of worse outcomes, while anti-inflammatory cytokines predicted improved scores. These results suggest that unilateral knee injury can result in a broader systemic inflammatory response that influences long-term outcomes in patients.