Xanthine oxidase inhibitors such as allopurinol and febuxostat have been the mainstay urate-lowering therapy (ULT) for treating hyperuricaemia in patients with gout. However, not all patients receiving oral ULT achieve the target serum urate level, in part because some patients cannot tolerate, or have actual or misconceived contraindications to, their use, mainly due to comorbidities. ULT dosage is also limited by formularies and clinical inertia. This failure to sufficiently lower serum urate levels can lead to difficult-to-treat or uncontrolled gout, usually due to poorly managed and/or under-treated gout. In species other than humans, uricase (urate oxidase) converts urate to allantoin, which is more soluble in urine than uric acid. Exogenic uricases are an exciting therapeutic option for patients with gout. They can be viewed as enzyme replacement therapy. Uricases are being used to treat uncontrolled gout, and can achieve rapid reduction of hyperuricaemia, dramatic resolution of tophi, decreased chronic joint pain and improved quality of life. Availability, cost and uricase immunogenicity have limited their use. Uricases could become a leading choice in severe and difficult-to-treat gout as induction and/or debulking therapy (that is, for lowering of the urate pool) to be followed by chronic oral ULT. This Review summarizes the evidence regarding available uricases and those in the pipeline, their debulking effect and their outcomes related to gout and beyond.
The lack of a functional uricase to metabolize uric acid and facilitate its elimination renders humans susceptible to hyperuricaemia and gout.
Uricases are foreign to the human immune system; thus, treatment with exogenous uricases can lead to the development of anti-drug antibodies, which can decrease the efficacy of uricases and increase the risk of infusion reactions.
Combination therapy of uricases with immunosuppressants decreases the incidence of anti-drug antibodies and increases the proportion of patients who respond to uricase treatment.
Screening for glucose-6-phosphate dehydrogenase deficiency before the first infusion of uricase is crucial.
Implementation of a ‘stopping rule’ for uricase treatment based on two sequential pre-infusion measurements of serum urate levels >6.0 mg/dl reduces the risk of infusion reactions.
Two uricases, rasburicase and pegloticase, are currently available, and several other uricases are in the drug development pipeline.
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N.S. declares that she has received a grant from Olatec and has been on advisory boards and acted as a consultant for ANI, Horizon Pharma, Novartis, Protalix and SOBI. F.P.-R. declares that he is an adviser for Anlylam, Arthriti and Protalix; a speaker for Menarini Central America; a member of Data and Safety Monitoring Board (DMSB) for Selecta/SOBI; does editorial work for Springer Healthcare, Wolters-Kluwer, Exploration Publications and the Spanish Foundation for Rheumatology; and has received grants from the Cruces Rheumatology Association. F.L. declares that he has been on advisory boards for Horizon Pharma, Novartis France and Olatec; is a member of DMSB for Olatec; does editorial work for Elsevier; is a CME speaker for Mayoly-Spindler, Menarini Central America and Novartis; and has received unrestricted educational grants from Horizon Pharma, Mayoly-Spindler, Novartis, Olatec and SOBI for the European Crystal Network workshops.
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Schlesinger, N., Pérez-Ruiz, F. & Lioté, F. Mechanisms and rationale for uricase use in patients with gout. Nat Rev Rheumatol 19, 640–649 (2023). https://doi.org/10.1038/s41584-023-01006-3