Presurgical immune biomarkers associated with pain intensity and pain interference recovery after total knee arthroplasty: findings from the PRIME-KNEE study

Chronic postsurgical pain (CPSP) prevalence after total knee arthroplasty (TKA) is >20%. Circulating immune biomarkers are associated with musculoskeletal pain but poorly understood as CPSP predictors. This prospective, longitudinal study of 203 patients undergoing TKA tested presurgical plasma biomarkers associated with 6-month CPSP, using approaches from geriatrics biomarker research: expected recovery differential (ERD; resilience outcome) and penalized, machine-learning regularization modeling (elastic net and LASSO regression). Forty-nine presurgical candidate biomarkers were considered. CPSP was operationalized using ERDs built around PROMIS pain intensity and pain interference, which quantified the difference between observed and expected recovery after accounting for demographic, comorbidity, reserve, and perioperative factors. Plasma/ERDs from ∼130 patients revealed 13 biomarkers with the highest selection stability criteria, and either positive or negative (+/–) associations with ERDs. Interleukin (IL) −5 (–) and Lipopolysaccharide-Binding Protein (LBP; +) were associated with both ERDs. Unique associations with pain intensity ERD included Cytomegalovirus-Specific IgG Negative (CMV IgG–; –), Macrophage Inflammatory Protein-1 Beta (MIP-1β; –), IL-12p70 (–), Cluster of Differentiation 30 (sCD30; –), Interferon alpha 2a (IFNα2a; +), and Leukemia Inhibitory Factor (LIF; +). Unique associations with pain interference ERD included Lipopolysaccharide (LPS; –), Activin A (–), IL-8 (–), Serum Amyloid A (SAA; –), and IL-7 (+). Protein-protein interaction and topological analyses suggest a centralized subnetwork with higher-than-expected connectivity involving IL-5, IL-7, IL-8, MIP-1β, and IFNα-2a, among others. This study proposes rigorous yet feasible approaches to expedite pain biomarker research and introduces presurgical biomarkers to consider in future TKA-CPSP biosignature derivation.