Analyses of plasma inflammatory proteins reveal biomarkers predictive of subsequent development of giant cell arteritis: a prospective study

Abstract

Objective To investigate the relation between biomarkers of inflammation and subsequent development of giant cell arteritis (GCA). Method Participants in the population-based Malmö Diet Cancer Study (MDCS; N = 30447), established 1991–1996, who were subsequently diagnosed with GCA, were identified in a structured process. GCA-free controls, matched for sex, year of birth, and year of screening were selected from the study cohort. Baseline plasma samples were analyzed using the antibody-based OLINK proteomics inflammation panel (92 inflammatory proteins). Analyses were pre-designated as hypothesis-driven or hypothesis-generating. In the latter, principal component analysis was used to identify groups of proteins that explain the variance in the proteome. Within components selected based on Eigenvalues, proteins with a factor loading of > 0.50 were investigated. Results 94 cases with a confirmed incident diagnosis of GCA (median 11.9 years after inclusion) were identified. Among biomarkers with a priori hypotheses, IFN-γ was positively associated with GCA (odds ratio (OR) per SD 1.52; 95% CI 1.00–2.30). Eight biomarkers in the hypothesis-generating analyses were significantly associated with development of GCA. Among these, higher levels of IFN-γ (OR 2.37; 95% CI 1.14–4.92) and MCP3 (OR 4.27; 95% CI 1.26–14.53) were particularly associated with increased risk of GCA in the subset sampled <8.5 years before diagnosis. Several other proteins known to be important for T cell function were also associated with GCA in these analyses, e.g. CXCL9, IL-2, CD40 and CCL25. Conclusion Elevated IFN-γ levels were found years prior to diagnosis of GCA. T cell activation may precede the clinical onset of GCA.

Pathogenesis of giant cell arteritis with focus on cellular populations

“…Innate check-point dysregulation contributing to GCA development may be influenced by metabolic factors ( 89 ). The importance of T-cell dysregulation has been further underlined by the recent demonstration of elevated T-cell related cytokines years before disease onset ( 78 ).…”

“…It has recently been demonstrated that plasma levels of IFN-γ and other proteins related to T cell function may be elevated years before clinical disease onset ( 78 ), further underlining the importance of this pathway and suggesting that it may drive very early disease mechanisms.…”

“…A more plausible hypothesis could be that an infection is the last part of the drama, where the infection causes an unpredictable and strong reaction of the immune system, because of the cumulative effect of other previous dysregulated interactions between the immune system and host tissues. On the other hand, the demonstration of elevated plasma IFN-γ levels years before GCA onset suggest that host responses to a range of different microbial pathogens may be involved in early stages of the disease process ( 78 ).…”

Biomarkers in the era of targeted therapy in giant cell arteritis and polymyalgia rheumatica: is it possible to replace acute-phase reactants?

“…Very interesting data are provided by a Swedish study on the biomarkers that were measured in people prior to the development of GCA (22). In this study, the authors used a large cohort of 30,447 patients-initially developed to study cancer-and identified 94 cases of incident GCA.…”

Systemic vasculitis: one year in review 2023

“…Novel biomarkers from translational may increase the probability to identify GCA among patients with new onset PMR. Among them angiopoietin-2/1 ratios and metalloproteinase-3 levels (22) as well as interferon-γ levels and T-cell activation (23) were identified and proposed. Another clinical challenge in GCA is represented by the possibility of distinguishing active from inactive disease.…”