In patients with tissue deposits of urate crystals, acute flares of gout develop more frequently after certain dietary triggers and in early uric acid lowering therapy (ULT). However, most acute flares of gout develop and recur variably and unpredictably. New gout inflammation biomarkers, and novel, rational, lab discovery-based therapeutics targeted to them, would advance care. Elevation of serum urate, though a biomarker for long-term prognosis in gout, has no clear role in assessing the inflammatory state in gout. Moreover, the only serum biomarker of inflammation in both acute and intercritical gout appears to be elevation of IL-8. Increasing the number of options for anti-inflammatory treatment for gout also is a central unmet need. Gouty inflammation is driven by innate immune responses to urate crystals, with “first signal” priming of the NLRP3 inflammasome in macrophage lineage cells by C5a, NF-kB transcription factor activation and a variety toll-like receptor 2 and 4 (TLR2, 4) ligands, and coupled “second signals” via NLRP3 inflammasome activation driving secretion of mature IL-1beta. Sources of variability in the capacity of urate crystals to cause inflammation will be reviewed in this talk. They include not simply exogenous dietary factors, but also constitutive “master” regulation of host inflammatory responses to urate crystals. I will discuss, in depth, AMP-activated protein kinase (AMPK), a druggable master regulator of urate crystal-induced inflammation and mediator of comorbidity. AMPK is one of several biosensors of changes in nutrition and cellular energy processes (eg, glycolysis, oxidative phosphorylation) that are emerging as therapy targets for controlling adaptive and innate immune inflammatory responses, exemplified by suppression of SLE using metformin. Last, I will summarize how metabolic regulation of innate inflammation is directly relevant to gout, since both hyperuricemia and clinical expression of gouty arthritis are influenced by highly prevalent metabolic co-morbidities and dietary factors, such as the linked co-morbidities obesity, metabolic syndrome and type II diabetes, and related caloric excesses.
Disclosure of Interest R. Terkeltaub Md Consultant for: Sobi, AZ, REVIVE, Relburn
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