An Update on the Pathology

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Gouty arthritis is an inflammatory disease initially triggered by the deposition of monosodium urate crystals into the joint space, developing into an inflammatory cascade resulting in the secretion of several proinflammatory cytokines and neutrophil recruitment into the joint. It is associated with debilitating clinical symptoms, functional impairments, and a substantial impact on quality-of-life.

Currently available agents are generally effective but associated with a number of adverse events and contraindications that complicate their use. Increased understanding of the inflammatory pathogenesis of gouty arthritis has paved the way for development of several new agents that may provide increased efficacy and reduced toxicity.

Chronic hyperuricemia is a prerequisite in the development of gouty arthritis. Uric acid is a weak acid present physiologically in its ionized form as urate, and it is a product of purine breakdown which is excreted to remove nitrogenous waste. Diet, biosynthesis and excretion maintain homeostasis of urate levels in the body; overproduction or, more commonly, insufficient renal clearance cause chronic hyperuricemia. This in turn leads to supersaturation of plasma urate, and at concentrations >6.8 mg/dL, monosodium urate (MSU) crystals can precipitate. When MSU crystal deposits near a joint are released into the joint space causing inflammation, the result is acute gouty arthritis.

Gouty arthritis is the most common inflammatory arthritis in males over the age of 40 years, but it is also one of the most misunderstood diseases. Hyperuricemia is a requirement to develop gouty arthritis. Upon oversaturation of serum urate, typically above 6.8 mg/dl, MSU can crystallize in tissue including the joint, giving rise to gouty arthritis. Phagocytosis of coated MSU crystals by macrophages leads to activation of the ‘inflammasome’, a cytosolic multiprotein complex. This in turn activates of a series of pro-inflammatory enzymes such as caspases promoting the maturation of IL-1 ß, a pro-inflammatory cytokine, culminating in neutrophil influx into the synovium that characterizes the highly inflammatory nature of acute gouty arthritis. Management of this condition involves treatment of the acute attack, addressing the underlying metabolic abnormality of the hyperuricemia, and providing prophylaxis to the patient to prevent recurrence until normouricemia is achieved. Here, serum urate lowering is usually accomplished by the use of xanthine oxidase inhibitors such as allopurinol or febuxostat, or intravenous pegloticase (uricase). Treatment of acute gout flares has historically included NSAIDS, colchicine, and corticosteroids, but a substantial proportion of especially elderly patients are either unresponsive to or intolerant of the use of these medications because of the significant co-morbidities such as renal failure, cardiovascular disease or being at risk for gastrointestinal bleeding. In these patients, the advent of IL-1 blockade represents a promising new treatment modality to treat acute gouty arthritis and prevent frequent painful flare-ups.

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Regards
Alex John