Proteomic Pathways that Lead to Gout Comorbidities

Gout is a pesky clinical gnat. It is relatively easily diagnosed due to its presentation in patients, its etiology and pathogenesis are well-understood, and a host of treatment options attack the condition at different angles. Yet, several areas of treatment continue to perplex. Why do flares of gouty arthritis occur infrequently despite the continuous presence of monosodium urate (MSU) crystals in the body? What proteins cause sodium in the MSU crystals to release in the body? And what relationship do pro-inflammatory cytokines have with gout co-morbidities, which can include cardiovascular disease and diabetes?

A recent meta-analysis in Arthritis & Rheumatology examined the systemic nature of gout with the goal of identifying proteomic pathways that could lead to comorbidities in gout patients. The analysis looked at three independent cohorts of 330 gout patients and compared them with 144 healthy individuals and 276 disease controls.

In particular, the analysis looked at circulating levels of the cytokines IL-8 (CXCL8), IL-1b, IL-6, IL-10, IL-12, and TNF-a—the “usual suspects” that are thought (in some cases, known) to be inflammatory mediators of MSU . Then, the researchers used proteome-wide analysis in a selection of samples to determine possible prognostic proteins for the development of comorbidities.

Compared to healthy and disease controls, patients with gouty arthritis (n=48) had significantly higher mean levels of CXCL8 (P&thinsp; <&thinsp;.001), whereas other cytokines were almost undetectable. Similarly, patients with intercritical (inactive) gout also showed high levels of CXCL8. CXCL8 was independently associated (P<.0001) with diabetes in intercritical gout patients. Proteome-wide analysis in gouty arthritis (n=18) and intercritical gout (n=39) revealed MRP8/14 as the protein with the greatest differential expression and correlation with CXCL8 (R² 0.49, P<.001), which was replicated in an independent cohort. The proteome of gout patients with high CXCL8 was associated with diabetes (OR, 95% CI; 16.5, 2.8-96.6) and cardiovascular disease (OR, 95% CI; 3.9, 1.0-15.3).

Previous research has shown that MRP8/14 is expressed and produced at a higher level by type 1 diabetes monocytes have been demonstrated in type 1 diabetes patients. The study authors conclude that circulating levels of CXCL8 levels are increased during both the arthritis and intercritical phases of gout, and that this coincides circulating proteomes associated with diabetes and cardiovascular disease risk. The study authors hope that this analysis—which confirms other findings&mdash;will lead to additional research on the roles of CXCL8 and MRP8/14 in patients with gout and their potential for developing comorbidities.