The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis

Abstract

Objectives Cardiovascular (CV) mortality in RA patients is 50% higher than in the general population. There is increasing recognition that systemic inflammation is a major driver of this. IL-6 is implicated in cardiovascular disease (CVD) in the general population but its role in CVD in RA is undefined. Of the two modes of IL-6 signalling, trans-signalling is pro-inflammatory whereas classical signalling is linked with inflammation resolution. This study examines the role of IL-6 trans-signalling in CVD in a mouse model and patients with RA. Methods Myography determined the effect of IL-6 trans-signalling blockade, using sgp130Fc, on aortic constriction in murine collagen-induced arthritis. Serum CCL2 and sVCAM-1 as soluble biomarkers of sIL-6R trans-signalling were investigated in a human cross-sectional study. An observational longitudinal study investigated the association between these biomarkers and progression of subclinical atherosclerosis in early RA by measuring carotid intima-media thickness (CIMT). Results sgp130Fc reduced arthritis severity, serum CCL2 and sVCAM-1 and restored vascular function in collagen-induced arthritis (CIA). In established RA, sVCAM-1 correlated with the 28-joint DAS (DAS28) and CV risk. In early RA, baseline DAS28 was associated with CIMT change at 6 months. CIMT ‘rapid progressors’ at 12 months had higher baseline sVCAM-1, haemoglobin A1c, cholesterol:high-density lipoprotein cholesterol ratio and LDL cholesterol. Conclusions IL-6 trans-signalling plays a pivotal role in vascular dysfunction in CIA. In early RA, sVCAM-1 was associated with progression of subclinical atherosclerosis. Inflammation from RA onset in CVD-susceptible individuals may accelerate atherosclerosis. IL-6 trans-signalling blockade may be beneficial to RA patients and perhaps for atherosclerosis in the general population.

Association of serum IL-30 and soluble GP130 with the risk of psoriasis vulgaris

“…27 Soluble GP130FC competitively inhibits the binding of IL-6 to its membrane-bound receptor and has therefore been used as an IL-6 antagonist in the clinical treatment of some immunological diseases. 28 This may explain our results of unaltered levels of soluble GP130 in psoriasis patients in comparison to the control group. Accordingly, we supposed that unaltered GP130 levels leads to enhanced IL-30 trans-signaling via IL27R and/or IL-6Ra, if IL-30 /CLF1 heterodimer has been formed.…”

Accelerated atherosclerosis in rheumatoid arthritis: a systematic review

“…42,45,78 Davies et al found a positive correlation between RA disease activity and sVCAM-1, and associated it with the role of IL-6 in mediating atherosclerosis in RA. 88 They went on to conclude that IL-6 trans-signaling plays an important role in vascular dysfunction in RA and blocking this pathway may be useful for RA patients. IL-1 is considered to be a proatherogenic cytokine as it stimulates SMC proliferation by autocrine induction of the platelet-derived growth factor (PDGF).…”

Non-pharmacological treatment in difficult-to-treat rheumatoid arthritis

“…In RA, the prevalence of different psychological problems like anxiety and depression is high ( 37 ), and even more pronounced in D2TRA ( 38 ). Depression was found to be 2–3 times more common in RA patients ( 39 ), it is considered as one of the most common comorbidity of RA ( 40 ) with common points in cytokine pattern ( 41 ), and there seems to be a bidirectional relationship between pain and depression ( 42 ).…”