The inflammatory process of gout and its treatment

Abstract

Gouty arthritis is a characteristically intense acute inflammatory reaction that erupts in response to articular deposits of monosodium urate (MSU) crystals. Important recent molecular biologic advances in this field have given us a clear picture of the mechanistic basis of gouty inflammation. The innate immune inflammatory response is critically involved in the pathology of gout. Specifically, MSU crystals promote inflammation directly by stimulating cells via Toll-like receptor signaling and by providing a surface for cleavage of C5 and formation of complement membrane attack complex (C5b-9), culminating in secretion of cytokines, chemokines, and other inflammatory mediators with a dramatic influx of neutrophils into the joint. Despite the detailed mechanistic picture for gouty inflammation, there are no placebo-controlled, randomized clinical studies for any of the therapies commonly used, although comparative studies have demonstrated that many nonsteroidal anti-inflammatory drugs are equivalent to indomethacin with respect to controlling acute gouty attacks. In general, the first line of anti-inflammatory therapy for acute gout is nonsteroidal anti-inflammatory drugs, and the selective cyclo-oxygenase-2 inhibitor celecoxib can be used where appropriate. The second line of treatment is glucocorticosteroids, given systemically (oral, intravenous, or intramuscular) or intra-articularly. Alternatively, synthetic adrenocorticotropic hormone is effective, partly via induction of adrenal glucocorticosteroids and partly via rapid peripheral suppression of leukocyte activation by melatonin receptor 3 signaling. The third line of treatment is oral colchicine, which is highly effective when given early in an acute gouty attack, but it is poorly tolerated because of predictable gastrointestinal side effects.

Figure 1

The innate immune response in recognition, uptake, and responses of cells to monosodium urate (MSU) crystals. As discussed in the text, recognition of the naked MSU crystal by the toll-like receptors 2 and 4 (TLR2, TLR4), which are normally involved in triggering innate host defense responses to infectious pathogens is a primary trigger of inflammatory and degenerative tissue reactions associated with gouty arthritis. TLR2, TLR4, and the TLR adaptor protein MyD88 promote ingestion of the naked MSU crystal by phagocytes. Downstream of TLR2 and TLR4 recognition of the MSU crystal, MyD88 transduces activation of the transcription factor NF-κB and the expression of a variety of pro-inflammatory mediators. Intracellular assembly of the cytosolic NALP3 (cryopyrin) inflammasome protein complex is subsequently triggered by delivery to the inflamamsome of ingested MSU crystals in phagocytes. The inflammasome assembly in response to MSU crystals triggers caspase-1 activation and the maturation and release of IL-1β in phagocytes. MSU crystal-induced (but not ATP-induced) NALP3 inflammasome protein complex assembly is suppressed by high concentrations of the microtubule inhibitor colchicine, suggesting that a high concentration of colchicine blocks delivery of the crystals to the NALP3 inflammasome AP, activator protein; iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase.