Abstract
In the panorama of inflammatory arthritis, gout is the most common and studied disease. It is known that hyperuricemia and monosodium urate (MSU) crystal-induced inflammation provoke crystal deposits in joints. However, since hyperuricemia alone is not sufficient to develop gout, molecular-genetic contributions are necessary to better clinically frame the disease. Herein, we review the autoinflammatory features of gout, from clinical challenges and differential diagnosis, to the autoinflammatory mechanisms, providing also emerging therapeutic options available for targeting the main inflammatory pathways involved in gout pathogenesis. This has important implication as treating the autoinflammatory aspects and not only the dysmetabolic side of gout may provide an effective and safer alternative for patients even in the prevention of possible gouty attacks.
Highlights
Many loci associated with gout are known to code for proteins directly involved in processing NLRP3 inflammasome, including membrane bound receptors, transcriptional regulators, ion channels, lipoproteins, and the inflammasome molecules (i.e., APOA1, APOC3, CARD8, CD14, NLRP3, PPARGC1B, P2RX7, and TLR4)
The TLR4 gene, coding for a transmembrane pattern recognition receptor, an important mediator of gouty inflammation, is highly polymorphic. rs2149356 is the only variant currently associated with increased risk of gout in Han Chinese and European populations and may play a regulatory role of TLR4 expression and IL-1 serum levels during flares [53]
P2X7 receptor implicated in inflammasome activation and probably a key regulator of IL-1β production by monosodium urate (MSU) crystals during acute gout flares, have been reported to be associated with gout: rs1653624, rs7958316, rs17525809, and rs3751142 [56]
Summary
Autoinflammation and autoimmunity are not sharply defined, as many diseases display features common to both conditions. This led to the concept of the immunological disease continuum, in which intermediate place was taken by polygenic diseases with prominent autoinflammatory and/or autoimmune components [2]. Gout is the most common inflammatory arthritis with about 2–4% of prevalence worldwide, mainly in men over 40 and in those with underlying comorbidities such as obesity, hypertension, coronary artery disease, diabetes, or metabolic diseases. Further autoinflammatory aspects of gout are the typically self-limiting nature of acute flares and the central role of inflammatory cytokines, such as interleukin (IL)-1β, suggesting that pro- and anti-inflammatory regulatory pathways are involved in gout [5].
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