Pegloticase response

Pegloticase is used to treat the high levels of uric acid associated with refractory gout. The use of pegloticase is reserved for individuals with symptomatic, chronic gout who have not responded to, or are unable to take, conventional gout treatments. Pegloticase is given once every 2 weeks as an intravenous infusion, and is given in a healthcare setting that is prepared to manage infusion reactions and anaphylaxis. Pegloticase is a pegylated urate oxidase – a modified version of the enzyme that catalyzes the oxidation of uric acid to 5-hydroxyisourate and hydrogen peroxide in most mammalian species. However, urate oxidase is not active in humans due to an inactivating mutation in the gene. Subsequent hydrolysis and decarboxylation of 5-hydroxyisourate leads to the formation of a more soluble metabolite (allantoin), which is then excreted by the kidneys. Red blood cells that lack the glucose-6-phosphate dehydrogenase (G6PD) enzyme are sensitive to oxidative damage caused by agents like hydrogen peroxide. Once exposed, the red blood cells become rigid, trapped, and are rapidly broken down (hemolysis). This can lead to a deficiency of mature red blood cells (hemolytic anemia) and the production of red blood cells with abnormally high levels of methemoglobin (methemoglobinemia). Approximately 400 million people worldwide have G6PD deficiency. Most of these individuals are asymptomatic. However, they are at risk of life-threating hemolytic reactions and methemoglobinemia if given oxidizing drugs such as pegloticase. Pegloticase is contraindicated in individuals with G6PD deficiency. The FDA-approved label states that individuals at higher risk for G6PD deficiency should be screened before starting pegloticase therapy, with specific examples including individuals of African, Mediterranean (including Southern European and Middle Eastern), and South Asian ancestry. Importantly, approximately 12% of African-Americans have G6PD deficiency. [from Medical Genetics Summaries]