Dexamethasone vs. placebo modulation of the perioperative blood immune proteome in patients undergoing total knee arthroplasty.

Abstract

Background: Pre- and post-operative immune status has gained interest in recent years, as it has been shown to be related to postoperative complications and recovery. The change in immune status has also been known to constitute a large part of the surgical stress response, and it has been speculated that immunomodulatory treatment by glucocorticoids may impact it. Profiling of the impact of specific surgeries and medications on immune status are therefore needed.

Methods: We characterized the postoperative blood immune proteome in 83 patients receiving either placebo (n = 20) or IV 24 mg dexamethasone (n = 60) preoperative before total knee arthroplasty (TKA). The primary outcome was the effect of dexamethasone on total knee arthroplasty surgical stress by comparing postoperative immune proteome in the dexamethasone group and the placebo group. Secondary outcomes were the surgical stress by total knee arthroplasty by comparing pre- to postoperative immune proteome in the placebo group, and the combined effect of surgical stress and dexamethasone by comparing pre- to postoperative immune proteome in the dexamethasone group. Characterization was performed with the Olink Explorer Inflammation panel on blood samples from the biobank for future research collected during the randomized, clinical DEX-2-TKA Trial. Protein change was reported as log2-fold-change and p-values were corrected a.m. Benjamini-Hochberg.

Results: The surgical stress (placebo) was characterized by a 4.7 log2-fold-change of IL6 (adjusted p-value < 0.01) and up-regulation of central immune signaling pathways and bone marrow mobilization. The combined effect of surgery and dexamethasone showed a less pro-inflammatory profile: IL6 2.5 log2-fold-change (adjusted p-value < 0.01), with decreased signaling for osteoclast activity and innate, immune cell reaction. The effect of dexamethasone showed upregulation of CSF3 (1.55 log2-fold-change, adjusted p-value < 0.01) and an inhibitory effect on both innate and adaptive immune response, immune cell reactivity and formation of extracellular matrix.

Conclusions: Preoperative dexamethasone indicated anti-inflammatory properties on both innate and adaptive immune response, while surgery was pro-inflammatory. the combination of total knee arthroplasty and dexamethasone inhibited pathways for osteoclast-activity, indicating possible implications on aseptic prosthesis loosening. Dexamethasone showed strong modulation of the surgical stress response following total knee arthroplasty and future studies must explore the clinical associations of these findings.

Trial registration: NCT03506789.