Gout is a chronic systemic inflammatory disease in which pro-inflammatory cytokines are elevated regardless of disease activity and strongly linked with comorbid diabetes and cardiovascular disease, a joint Dutch-New Zealand study has found.
“It shows once and for all that gout is a chronic disease with continuous low-grade inflammation driving comorbidities such as diabetes and CVD,” lead author Professor Tim Radstake, from the University Medical Center Utrecht told the limbic.
“It also suggests that other mechanisms than the activation of the inflammasome underlie these co-morbidities”.
“These findings have a major impact on our understanding of the pathogenesis of gout and its comorbidities.”
Gout’s association with widespread urate deposition (tophi), renal disease, the metabolic syndrome and cardiovascular disease strongly suggest it is a systemic condition rather than a localised joint problem.
Despite the strong links, there has been little research on systemic inflammatory markers in patients with either acute attacks or while the symptoms are dormant.
In the first step of the study published in Arthritis and Rheumatology 48 Dutch patients with gouty arthritis were found to have higher levels of IL-8 (now also called CXCL8) than healthy controls or patients with other inflammatory conditions including rheumatoid arthritis, systemic sclerosis and dermatitis.
The researchers then used proteome analysis to explore whether there was a distinctive pattern of protein expression in patients with high IL-8 levels, and found elevated concentrations of a protein called MRP8/14.
In turn, high levels of the protein increased the risk of cardiovascular disease four-fold and the risk of diabetes 16-fold.
The results were replicated in two cohorts of New Zealand and Dutch patients with ‘intercritical’ gout.
IL-8 has a pivotal role in cardiovascular disease, probably reflecting activation of endothelial cells, and it is found in high levels in atherosclerotic plaque.
It is an independent predictor of outcomes in patients with coronary artery disease and may help explain the links between obesity, the metabolic syndrome and diabetes.
MRP8/14 is a toll-like receptor (TLR) 4 agonist and has also been implicated in cardiovascular disease.
“Activation of macrophages due to TLR stimulation by monosodium urate crystals in gout may form the initiating event,” the researchers said.
“This concept would…link MSU crystals with chronic low-grade inflammation and risk for CVD, diabetes and other comorbidities so often observed.”
Both IL-8 and MRP8/14 could potentially prove useful as biomarkers to identify patients with gout who are at the greatest risk from cardiovascular disease and diabetes.