Gout, tophi and the wonders of NETs.

Abstract

Editorial ‘If I didn’t work on lupus, I would work on gout,’ I tell my fellow as we stand outside the room of a patient with an acute flare, his knee red and swollen. I have made this assertion many times, eliciting surprise if not mystification since lupus, the main focus of my research, and gout seem polar opposites. Lupus is a chronic antibody-mediated disease while gout is an acute cytokine-mediated disease. What I say next would prompt genuine concern about my mental well-being. ‘And, if I worked on gout, I would study the tophus,’ I say decisively. Lest you think I am going off the rails, I believe that study of the tophus holds important insights for immunology. While interest in the tophus has surged recently as an outcome measure in treatment, it is often an afterthought, infrequently analyzed. Few studies have characterized tophi by modern immunofluorescence or electron microscopic techniques. Nevertheless, recent studies indicate that the tophus may be a goldmine to find real gems on immune regulation. Such studies are also strengthening what to me has always been quite simple and obvious: the lupus–gout connection. Despite differences in clinical course, both lupus and gout concern the response to single molecules. These molecules are linked biochemically and, indeed, one is the product of the other. For lupus, the molecule is DNA; for gout, it is uric acid. DNA is built of purines (and pyrimidines), with uric acid a byproduct of purine degradation. Furthermore, both DNA and uric acid are damageassociated molecular patterns, released during cell death to signal danger and trigger inflammation. Hence, my attraction to these diseases. It is in the context of immune regulation that the tophus takes center stage. Monosodium urate (MSU), the crystalline salt form of uric acid, is one of the most proinflammatory chemicals ever found. In the tophus core, MSU should be present at enormous concentrations, with milk of urate essentially a suspension of gout crystals. Yet, despite the clear and present danger of so