Linking Circulating Metal Levels to Cytokine Signatures in Total Joint Arthroplasty Patients

Abstract

Arthroplasty may significantly improve the quality of life; however, wear and corrosion of metallic biomaterials can lead to the release of metal ions and particles, contributing to immune responses. Circulating metals may influence cytokine production, but systemic biomarkers of implant-related inflammation remain elusive. This study aimed to quantify systemic metal levels and cytokines to identify potential immunological signatures in patients exposed to arthroplasty metals. Peripheral blood samples from 150 patients scheduled for either primary or revision arthroplasty were analyzed. Whole blood multi-metal levels were quantified by inductively coupled plasma mass spectrometry. Plasma levels of 47 cytokines were quantified using a bead-based multiplex immunoassay. Cytokine patterns were examined via clustering and correlated with metal levels, adjusting for age, sex, prosthetic joint infection, lymphocyte count, C-reactive protein levels, and season. Blood levels of cobalt, chromium, titanium, niobium, and zirconium were significantly elevated in patients with arthroplasty implants, compared to arthroplasty-naïve controls. Selective correlations were observed, notably cobalt with IL-8 and multiple metals with IL-15. Cytokine clustering identified four distinct modules representing systemic immune activity. Multivariable linear regression modeling revealed associations of metal exposure with IL-1RA, IL-8, IL-15, and the proinflammatory cluster after adjusting for age, sex, periprosthetic joint infection status, inflammation markers, and season. This study shows that arthroprosthetic metal exposure is associated with systemic elevation of selective cytokines. Blood-based cytokine profiles may serve as biomarkers for monitoring implant-related immune activation, providing insights into mechanisms of systemic inflammation, yet must be interpreted within the context of multifactorial influences.