Inflammation mediates approximately one quarter of excess relative all-cause mortality in persons with rheumatoid arthritis: the Trøndelag Health Study

Abstract

Inflammation may contribute to excess mortality in rheumatoid arthritis (RA) patients. We investigated associations to all-cause mortality of the inflammation markers high-sensitivity C-reactive protein (CRP), lactoferrin (neutrophil activation marker), and neopterin (monocyte activation marker). From the population-based Trøndelag Health Study (3rd wave 2006-2008), 316 RA patients and 43,579 controls were included. Lactoferrin and neopterin were quantified in a nested cohort (n = 283 RA patients, n = 3698 controls). Follow-up was until death found by linkage to the Norwegian Cause of Death Registry or 31.12.2018. All-cause mortality was analyzed using Cox regression and Cox regression-based mediation analysis. Having RA (hazard ratio (HR): 1.25, 95%CI: 1.00, 1.56, p = 0.048), and CRP ≥ 3 mg/L (HR: 1.50, 95%CI: 1.41, 1.60, p < 0.001) were associated with all-cause mortality. The overall excess relative mortality risk of having RA was 38%. CRP ≥ 3 mg/L mediated approximately 1/4 of this risk (p < 0.001). In the nested cohort, CRP ≥ 3 mg/L (HR: 1.51, 95%CI: 1.26, 1.80, p < 0.001) and neopterin (HR: 1.17, 95%CI: 1.01, 1.36, p = 0.031) were associated with all-cause mortality. In conclusion, CRP levels ≥ 3 mg/L mediated approximately a quarter of the 38% excess relative all-cause mortality risk associated with RA. Using definitions of RA remission with emphasis both on joint status and the level of general inflammation may help guide the most efficient treatment regimens.

Figure 1

Participant inclusion and exclusion. Participants in the main analysis including C-reactive protein, and the nested cohort study including the biomarkers C-reactive protein, lactoferrin, and neopterin. Missing variables: C-reactive protein (1.5%), body mass index (0.8%), total cholesterol (2.9%), HDL cholesterol (2.9%), smoking (11.3%). HUNT3; 3rd wave of the Trøndelag Health Study (2006–2008).

Figure 2

Analytical models. Panel a: In Cox regression, the independent associations with all-cause mortality of each of the explanatory variables presence of rheumatoid arthritis and C-reactive protein concentration ≥ 3 mg/L were investigated. Panel b: In the mediation analysis, the direct association with all-cause mortality of rheumatoid arthritis was investigated (), as well as the indirect effect of rheumatoid arthritis mediated by inflammation, using C-reactive protein concentration ≥ 3 mg/L as biomarker (). Both final models were adjusted for body mass index, diabetes, hypertension, smoking, and total cholesterol.