Interleukin 6 Inhibition and Coronary Artery Disease in a High-Risk Population: A Prospective Community-Based Clinical Study

Abstract

Background: Atherosclerosis is a chronic inflammatory disease, with interleukin 6 (IL-6) as a major player in inflammation cascade. IL-6 blockade may reduce cardiovascular risk, but current treatments to block IL-6 also induce dyslipidemia, a finding with an uncertain prognosis.

Methods and results: We aimed to determine the endothelial function responses to the IL-6-blocking agent tocilizumab, anti-tumor necrosis factor α, and synthetic disease-modifying antirheumatic drug therapies in patients with rheumatoid arthritis in a 16-week prospective study. Sixty consecutive patients with rheumatoid arthritis were enrolled. Tocilizumab and anti-tumor necrosis factor α therapy were started in 18 patients each while 24 patients were treated with synthetic disease-modifying antirheumatic drugs. Forty patients completed the 16-week follow-up period. The main outcome was flow-mediated dilation percentage variation before and after therapy. In the tocilizumab group, flow-mediated dilation percentage variation increased statistically significantly from a pre-treatment mean of (3.43% [95% CI, 1.28-5.58] to 5.96% [95% CI, 3.95-7.97]; P=0.03). Corresponding changes were 4.78% (95% CI, 2.13-7.42) to 6.75% (95% CI, 4.10-9.39) (P=0.09) and 2.87% (95% CI, -2.17 to 7.91) to 4.84% (95% CI, 2.61-7.07) (P=0.21) in the anti-tumor necrosis factor α and the synthetic disease-modifying antirheumatic drug groups, respectively (both not statistically significant). Total cholesterol increased significantly in the tocilizumab group from 197.5 (95% CI, 177.59-217.36) to 232.3 (201.62-263.09) (P=0.003) and in the synthetic disease-modifying antirheumatic drug group from 185.8 (95% CI, 169.76-201.81) to 202.8 (95% CI, 176.81-228.76) (P=0.04), but not in the anti-tumor necrosis factor α group. High-density lipoprotein did not change significantly in any group.

Conclusions: Endothelial function is improved by tocilizumab in a high-risk population, even as it increases total cholesterol and low-density lipoprotein levels.

Keywords: dyslipidemia; endothelial function; inflammation; tocilizumab.

Figure 1

Flow‐mediated dilation percentage variation (FMD%) after 16 weeks of therapy. ^● P<0.05; 16‐week represents second assessment. A, Box plot graphic: Tocilizumab FMD% variation. B, Box plot graphic. Anti–tumor necrosis factor (Anti‐TNF) FMD%. C, Box plot graphic. Synthetic disease‐modifying antirheumatic drug (sDMARD) FMD%.

Figure 2

Changes in plasma lipoproteins and triglycerides behavior after 16 weeks of therapy. A, Box plot graphic. Total cholesterol levels. B, Box plot graphic. Triglycerides levels. C, Box plot graphic. High‐density lipoprotein cholesterol (HDL‐C) levels. D, Box plot graphic. Low‐density lipoprotein (LDL‐C) levels. ^● P<0.05; ^▲ P<0.01and ≥0.001; ^◊ P<0.001; 16‐week represents second assessment. anti‐TNF indicates anti–tumor necrosis factor; DMARD, synthetic disease‐modifying antirheumatic drug; TC, total cholesterol; TCZ, tocilizumab.

Figure 3

Changes in disease activity scores and functional damage after 16 weeks of therapy. A, box plot graphic for disease activity score changes. B, Box plot graphic for functional damage behavior. ^● P<0.05; ^▲ P<0.01and ≥0.001; ^◊ P<0.001; 16‐week represents second assessment. anti‐TNF indicates anti–tumor necrosis factor; CRP, C‐reactive protein; DMARD, synthetic disease‐modifying antirheumatic drugs; TCZ, tocilizumab.