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Objectives and questions: Arthroplasty substantially improves patients’ quality of life, yet wear and corrosion of metallic implant components can result in the release of metal ions and particles, potentially triggering immune responses. Although local and systemic effects of metal release have been described, the systemic consequences of metal exposure in arthroplasty patients remain poorly understood, particularly regarding their potential impact on systemic inflammation. Reliable systemic biomarkers to assess metal-related immune alterations are still lacking. This study aimed to quantify metal levels and cytokines in peripheral blood to investigate how arthroplasty-related metal exposure alters systemic inflammatory patterns. The objective was to identify systemic cytokine signatures that may serve as candidate markers of metal-associated immune activation.

Material and methods: In the course of this single-center observational study, peripheral blood samples from 150 patients scheduled for primary or revision arthroplasty (hip, knee or shoulder) were analysed. Patients without any pre-existing implant (N=39) and patients undergoing revision arthroplasty (N=111), including septic (N=16) and aseptic (N=95) revision cases, were assigned. Whole blood levels of 10 arthroplasty-relevant metals were quantified by mass spectrometry, and plasma levels of 47 cytokines were measured using a multiplex immunoassay. Cytokine patterns were assessed by clustering and correlated with metal levels. Associations were evaluated using multivariable linear regression adjusting for age, sex, prosthetic joint infection, lymphocyte count, CRP, and season.

Results: Systemic levels of cobalt, chromium, titanium, niobium, and zirconium were significantly higher in patients with arthroplasty implants compared with implant-naïve patients. Selective associations were observed, most notably between cobalt and IL-8 and between several metals and IL-15. Cytokine clustering revealed four distinct immune modules, including a proinflammatory cluster enriched in patients with implants. Multivariate linear regression demonstrated that metal exposure was associated with IL-1RA, IL-8, IL-15, and the proinflammatory cluster, while age, CRP levels, PJI status, and seasonal variation additionally contributed to IL-8, IL-15, and cluster variability. IL-1RA levels were not significantly influenced by these predictors.

Discussion and conclusions: Arthroplasty-related metal exposure was associated with selective systemic cytokine elevations, most prominently IL-8, IL-15, and IL-1RA. These mediators reflect neutrophil chemotaxis (IL-8), adaptive lymphocyte activation (IL-15), and compensatory anti-inflammatory regulation (IL-1RA), indicating a low-grade but measurable systemic immune response in exposed patients. Blood-based cytokine signatures may therefore serve as complementary biomarkers of implant-related immune activation.