Background/Purpose: Rheumatoid arthritis (RA) and atherosclerosis are chronic inflammatory diseases that share many biological features.  Prevalence of atherosclerosis is increased by approximately 2-fold in RA, with at least 2 prominent molecular links between the two diseases: IL6 and TNFα signaling.  Elevated circulating IL6 is an independent risk factor for cardiovascular disease and correlates with RA disease progression in patients. To test the hypothesis that compounds used for the treatment of RA decrease vascular inflammation under atherogenic conditions.

Methods: To elucidate the impact of RA treatments on vessel wall health, a novel in vitro human surrogate system that co-cultures human endothelial (EC) and smooth muscle cells (SMC) was used.  Atheroprone flow conditions were applied, based upon human hemodynamic blood flow from the carotid bifurcation, a site prone to developing atherosclerosis.  Atherogenic risk factors were added to the culture medium, including in vivo circulating concentrations of oxidized LDL (oxLDL) and TNFα.  In addition, soluble IL-6 receptor (sIL6R) was added at a concentration typically seen in patient sera.  RNA sequencing and multiplex protein assays were used to perform transcriptomic and bioanalytical pathway analyses of the response of the human surrogate system. We compared treatments that target pathogenic RA pathways including anti-IL6 and anti-IL6 receptor antibody (sirukumab or tocilizumab, respectively), anti-TNFα antibody (adalimumab) and a small molecule inhibitor of JAK (tofacitinib) at C_min doses. 

Results: Using this model, the combination of sIL6R, TNFα and oxLDL induced a robust transcriptional response of inflammatory genes under atheroprone hemodynamics compared to control conditions without sIL6R or TNFα and with non-oxidized LDL.  The anti-IL6/IL6R treatments (sirukumab, tocilizumab) significantly improved the vascular health phenotype relative to control IgG treatment.   Both sirukumab and tocilizumab dramatically decreased adhesion molecule gene expression and NFkB-dependent genes while simultaneously increasing vasculoprotective responses such as eNOS and KLF2 expression, and promoting a contractile SMC phenotype. Adalimumab showed a weaker but similar trend compared to IL6 inhibition, while tofacitinib was not effective in suppressing inflammation or promoting vascular health. Sirukumab and tocilizumab were more effective in suppressing TNFα signaling than adalimumab.  Although broadly comparable, sirukumab was more potent than tocilizumab in suppressing inflammation and promoting vascular health.   

Conclusion: These data suggest that the IL6 pathway inhibitors (sirukumab and tocilizumab) potently suppress inflammation and promote vascular health in an in vitro model of RA-associated cardiovascular disease.  In contrast the TNFa inhibitor, adalimumab, and JAK inhibitor, tofacitinib, were less effective in alleviating the disease phenotype.  Collectively, the data suggest that IL6 inhibition may provide vascular protection in patients with RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-anti-il-6-antibody-sirukumab-inhibits-vascular-inflammation-in-a-human-surrogate-model-of-atherosclerosis/