Serum S100A8/A9 and MMP-9 levels are elevated in systemic lupus erythematosus patients with cognitive impairment

Front Immunol. 2024 Jan 25:14:1326751. doi: 10.3389/fimmu.2023.1326751. eCollection 2023.

Abstract

Objective: Cognitive impairment (CI) is one of the most common manifestations of Neuropsychiatric Systemic Lupus Erythematosus (NPSLE). Despite its frequency, we have a limited understanding of the underlying immune mechanisms, resulting in a lack of pathways to target. This study aims to bridge this gap by investigating differences in serum analyte levels in SLE patients based on their cognitive performance, independently from the attribution to SLE, and exploring the potential for various serum analytes to differentiate between SLE patients with and without CI.

Methods: Two hundred ninety individuals aged 18-65 years who met the 2019-EULAR/ACR classification criteria for SLE were included. Cognitive function was measured utilizing the adapted ACR-Neuropsychological Battery (ACR-NB). CI was defined as a z-score of ≤-1.5 in two or more domains. The serum levels of nine analytes were measured using ELISA. The data were randomly partitioned into a training (70%) and a test (30%) sets. Differences in the analyte levels between patients with and without CI were determined; and their ability to discriminate CI from non-CI was evaluated.

Results: Of 290 patients, 40% (n=116) had CI. Serum levels of S100A8/A9 and MMP-9, were significantly higher in patients with CI (p=0.006 and p=0.036, respectively). For most domains of the ACR-NB, patients with CI had higher S100A8/A9 serum levels than those without. Similarly, S100A8/A9 had a negative relationship with multiple CI tests and the highest AUC (0.74, 95%CI: 0.66-0.88) to differentiate between patients with and without CI.

Conclusion: In this large cohort of well-characterized SLE patients, serum S100A8/A9 and MMP-9 were elevated in patients with CI. S100A8/A9 had the greatest discriminatory ability in differentiating between patients with and without CI.

Keywords: MMP-9 (matrix metalloproteinase 9); S100A8/A9; cognitive impairment; neuropsychiatric systemic lupus erythematosus (NPSLE); systemic lupus erythematosus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calgranulin A
  • Calgranulin B
  • Cognitive Dysfunction* / diagnosis
  • Humans
  • Lupus Erythematosus, Systemic* / complications
  • Lupus Erythematosus, Systemic* / diagnosis
  • Matrix Metalloproteinase 9 / metabolism

Substances

  • Calgranulin A
  • Calgranulin B
  • Matrix Metalloproteinase 9
  • S100A8 protein, human
  • S100A9 protein, human
  • MMP9 protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This project is funded by grants from the Arthritis Society of Canada, Canadian Institutes of Health Research, Physician’s Services Incorporated, the Province of Ontario Early Research Award, and the Lupus Research Alliance. CM-G is supported by the Gary S. Gilkeson Career Development Award from the Lupus Foundation of America and a Diversity Award from the Lupus Research Alliance. ZT is supported by the Department of Medicine, University of Toronto. ZT’s laboratory is supported by Lupus Ontario, the Schroeder Arthritis Institute and donations from the Kathi and Peter Kaiser family, the Lou and Marissa Rocca family and the Stacey and Mark Krembil family. He also holds the Dr. Murray B. Urowitz Chair in Lupus Research at UHN. JW is supported by a Pfizer Chair Research Award. The authors declare that this study received funding from Pfizer, the Kathi and Peter Kaiser family, the Lou and Marissa Rocca family, and the Stacey and Mark Krembil family. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.