What can asymptomatic hyperuricaemia and systemic inflammation in the absence of gout tell us?

Is uric acid a biomarker or does it have a pathophysiological role in driving systemic inflammation? This editorial refers to Hyperuricaemia elevates circulating CCL2 levels and primes monocyte trafficking in subjects with inter-critical gout, by Rebecca Grainger A. et al. Rheumatology 2013; doi: 10.1093/rheumatology/kes326, on pages 1018–1021. Acute gout can be accompanied by systemic signs of inflammation, with fever, leucocytosis and elevation of high-sensitivity CRP in the blood. Many believe that systemic signs are a reflection of the intense local inflammatory reaction of monocytes and macrophages with urate crystals within the synovium, leading to the release of ILs and other inflammatory cytokines that cause systemic inflammation. In this issue of Rheumatology, Grainger et al. [1] present a study that reports on patients with hyperuricaemia who do not experience an episode of gout but who show signs of systemic inflammation. Specifically, they reported that serum monocyte chemoattractant protein-1 (MCP-1) and CD14-positive monocytes were elevated in patients with elevated serum urate levels compared with normouricaemic controls. Moreover, elevation of these parameters was present in patients with a history of acute and chronic gout who did not have a gout attack (intercritical period) as well as in those who have never had gout (asymptomatic hyperuricaemia). The importance of this observation is that it suggests that the presence of elevated serum urate may represent the presence of low-grade systemic inflammation. Other researchers have also linked high serum urate levels with systemic inflammation. In a population of 957 older Italian patients, Ruggiero et al. [2] reported that elevated serum urate in the absence of gout was strongly associated with markers of systemic inflammation, including leucocyte count, CRP and various serum levels of inflammatory cytokines (including CRP, IL-6, IL-1ra, IL-18 and TNF-α). The same group conducted a separate study of 892 Italian adults who were followed up for 3 years and found that serum urate independently predicted the subsequent level of serum CRP at follow-up [3]. At least three different mechanisms might account for this strong relationship of serum urate with systemic inflammation. First, systemic inflammation could be a reflection of a systemic reaction that may occur subclinically to low-grade inflammation to urate crystals in joints. Second, it is now well accepted that the resolution of an attack of gout does not result in dissolution of the urate crystals in the synovium, but rather a low-grade inflammation may continue despite no symptoms being observed by the patient. A recent ultrasound study suggests that low-grade gouty involvement of joints may also occur in patients with asymptomatic hyperuricaemia who have never had an episode of gout [4]. Thus the systemic inflammation may represent a systemic spillover from local inflammation to urate crystals. There is also evidence that soluble uric acid may have direct proinflammatory effects, including stimulating the production of CRP and MCP-1 in vascular cells through a mechanism that involves activation of NF-κB and mitogen-activated protein (MAP) kinases [5, 6]. Soluble uric acid can also stimulate the release of Weibel–Palade bodies with the release of IL-8 and angiopoietin-2 via a Toll-like receptor-4-dependent mechanism [7]. Although uric acid is an antioxidant in the extracellular environment, when uric acid enters vascular cells or adipocytes it induces pro-oxidative effects mediated in part by activation of the NADPH oxidase system and stimulating mitochondrial oxidative stress [8]. Most downstream signalling mechanisms triggered in response to uric acid, such as activation of MAP kinases and NF-κB, can be blocked by superoxide scavengers or inhibitors of NADPH oxidase [5]. Whether soluble uric acid can induce activation of the NALP3 inflammasome, as can be observed with urate crystals, is still unknown. The association of uric acid with systemic inflammation possibly relates to a separate mediator system that both drives inflammation and increases serum urate levels. One way to determine whether uric acid might have a causal role in systemic inflammation would be to evaluate the effect of lowering serum urate on markers of systemic inflammation. This was a drawback of the article by Grainger et al. [1], and hence their conclusion overstates their findings. However, there are an increasing number of pilot studies suggesting that lowering serum urate with either xanthine oxidase inhibitors or uricosurics can improve markers of systemic inflammation under various conditions (Table 1) [9–13]. For example, lowering the serum urate with allopurinol has been reported to lower CRP in both hypertensive patients [12] and those with chronic kidney disease [10], to lower intercellular adhesion molecule-1 (sICAM-1) in patients with ischaemic stroke [13] and to lower plasma MPO levels in those with metabolic syndrome [9]. Lowering of serum urate by benzbromarone has been reported to reduce circulating TNF-α in patients with heart failure [11]. Lowering serum urate in experimental models of metabolic syndrome and kidney disease is also associated with less inflammation in adipose tissue and the kidney. Not all studies have observed improvements in inflammation with lowering of serum urate, and clearly larger trials are needed. Nevertheless, there is increasing evidence that hyperuricaemia may be a mediator rather than a consequence of the systemic inflammatory response. Effect of lowering serum urate on inflammation-related markers CKD: chronic kidney disease; RCT: randomized controlled trial; us-CRP: ultra-sensitivity CRP; hs-CRP: high-sensitivity CRP. Effect of lowering serum urate on inflammation-related markers CKD: chronic kidney disease; RCT: randomized controlled trial; us-CRP: ultra-sensitivity CRP; hs-CRP: high-sensitivity CRP. Elevated serum urate is a consistent and independent risk factor for hypertension, metabolic syndrome, fatty liver, diabetes and kidney disease. One potential explanation for how uric acid might contribute to all these conditions would be if uric acid induced systemic inflammation. Studies such as that by Grainger et al. [1] provide evidence that elevated serum urate is associated with low-grade systemic inflammation even in the absence of gout. Future studies are necessary before one can definitively state whether uric acid is simply a biomarker or whether it has a true pathophysiological role in driving systemic inflammation. If the latter is true, uric acid could emerge as one of the most important cardiovascular risk factors ever identified. Disclosure statement: R.J.J. has patent applications related to lowering uric acid as a means to prevent or treat features of the metabolic syndrome. R.J.J. also has a patent on lowering uric acid with allopurinol for the treatment of hypertension. R.J.J. also has two books, The Sugar Fix (Rodale, 2008) and The Fat Switch (mercola.com, 2012), that discuss the role of uric acid and fructose in the obesity epidemic. All other authors have declared no conflicts of interest.