THE ROLE OF aggNETs IN GOUT
WITH PROFESSOR GEORG SCHETT, MD
I think the biggest misconception is that gout is the acute gout attack. Full stop. After the stop of the gout attack, gout has not stopped, in fact, because the uric acid crystals are still there.
It’s a kind of rethinking of the nature of gout as a more chronic disease and a damage-inducing disease, and how you can prevent damage by early treatment.
Gout is different from, for instance, rheumatoid arthritis. In rheumatoid arthritis, you start with inflammation, you get arthritis, and it doesn’t stop. So, there is a failure of resolution of disease. Whereas in gout, you have an enormous capacity to resolve it.
And I think we were intrigued by the fact that all the research in gout is very much addressing the activation of inflammation, which is of course very important, but the second phase, how gout resolves, has largely been completely elusive.
Uric acid crystals, although they’re not living organisms, like bacteria, they use similar receptors on the surface of immune cells.
So, the immune system recognizes strange things like bacteria or uric acid crystals. And that stimulates the immune system, to clear these agents, which potentially provide harm to the organism.
When a neutrophil engages a crystal, the neutrophils die by a specific form of cell death, which is called NETosis. That stands for neutrophil extracellular trap formation. The neutrophil disintegrates and evaporates, if you want. The DNA are basically put outside the cell. The extracellular DNA forms large clusters.
And these aggregated NETs are essentially anti-inflammatory structures. To contain the problem, aggNETs cleave inflammatory cytokines, reduce local concentrations of the inflammatory cytokines, and thereby also stop the pain response.
But after the stop of the gout attack, gout has not stopped, in fact. Because the uric acid crystals are still there.
You can see strings around. And this is nothing else than extracellular DNA, and you can see how nicely these extracellular DNA form a tophus-like structure.
Tophi are structures where basically uric acid crystals cluster together in a very dense way. They can be very small, microscopically small, and they can be very large.
The typical, classical perception of tophaceous gout is if you see a tophus. Well that’s clearly a sign that the urate burden is high in a patient with palpable, visible tophi. I think that’s, like with icebergs—it’s just the tip of the iceberg.
You only see the surface, and there is a lot more crystal burden actually, in patients when you look, for instance, with imaging techniques like ultrasound, also dual-energy CT, where you can pick up actually all the tophi, which are deposited in the tissue. You can’t see with your eye.
I think, uric acid crystal deposits are always dangerous, because they tend to destroy the neighboring tissue. And depending where they are localized, they either destroy for instance the bone, leading to bone erosion or osteophyte.
And that’s the damage which is usually irreversible. While you can resolve a tophus very well, you probably do not get rid of erosions and osteophytes and structural changes.
And I think that’s telling us that, we have to treat gout, we have to recognize gout early, and treat it early. Because that would prevent damage. So, for me, tophus clearance is the ultimate treatment goal for a gout patient.
So, the lower the uric acid level is, the better it is. Uric acid levels below 3 mg/dL I think are very good, to allow relatively fast resolution of tophi.
Since we have pharmacological tools to remove these crystal deposits, this is very important, because we can really treat the patient, we can help the patient.
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