201: Plasma Biomarkers Predict Post-Operative Pain after Total Knee Arthroplasty: Results from PRIME-Knee

Topic: Clinical Science
Subtopic: Pain category (ICD-11), Chronic postsurgical pain, Developing methodology/technology, Neuroimmunology, Pain in special populations (e.g. neonates, children, teens, elderly, neurodegenerative diseases)

Background and Aims: Over 20% of older adults after total knee arthroplasty (TKA) report persistent post-operative pain (POP; post-surgical pain ≥ 6 months). TKA POP screening is mostly limited to self-reported measures like pre-operative pain intensity. Blood-based biomarkers, while promising, require a novel approach of data reduction and validation to isolate from inherent patient-specific confounders (age-related biodiversity, comorbidity). We applied such an approach in PRIME-Knee, a prospective cohort study of 203 patients undergoing elective unilateral TKA at Duke. The purpose of PRIME-Knee was to identify predictive biomarkers of resilience outcomes like pain recovery, function, and falls.

Methods: Pre-operative blood assays produced 48 immune/aging candidate biomarkers that were quantified using immunoassays and custom multiplex panels. Concentrations below detection thresholds were imputed; continuous biomarkers were log-transformed and standardized. Six-month outcomes were expected recovery differential (ERD) between actual POP (via PROMIS pain intensity, pain interference) and predicted POP (via elastic net penalized regression, leave-one-out cross-validation; incorporates demographic, pre-operative pain, psychological, social, and comorbidity variables). Lastly, a LASSO penalized regression pipeline (200 resampled datasets combining two different resampling techniques [bootstrap, complementary pairs] and five different LASSO penalties) identified a stable set of pre-operative biomarkers that consistently predicted POP outcomes.

Results: Thirteen of 48 biomarkers met the highest LASSO model selection criteria (predictive in 10 out of 10 interim stable sets, for at least one POP outcome). Interferon alpha 2a (IFNa2a), interleukin-5 (IL-5), and interleukin-7 (IL-7) were deemed most stable in predicting POP outcomes. A one SD increase in IFNa2a led to >0.20 SD improvement in pain intensity ERD; log IL-5 >0.30 SD improvement in pain intensity and interference ERDs; and log IL-7 >0.20 SD improvement in pain interference ERD.

Conclusions: Among older adults undergoing TKA, POP is both highly common and difficult to predict. The current study introduces a novel approach that was adopted from geriatric resilience research (ERD, LASSO penalized regression pipeline), to more rigorously isolate pre-operative candidate plasma biomarkers from age-related biodiversity and comorbidity confounders. Future studies in this program will test the validity of the identified biomarkers (IFNa2a, IL-5, IL-7) in TKA POP prediction; and expand prediction to include modifiable peri- and post-operative mediation.

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Presenting Author: Corey B. Simon, DPT, PhD
Submitting Author: Corey Simon

Senior Author: Cathleen Colón-Emeric, MD

IASP 2026 Global Year theme of Neuropathic Pain: No