Abstract
BackgroundPegloticase is a recombinant mammalian uricase conjugated to polyethylene glycol approved in the United States for treatment of chronic refractory gout. It can profoundly decrease serum urate to < 1 mg/dl. In patients receiving pegloticase who did not generate high-titer antidrug antibodies (responders), the serum urate remained low for the duration of therapy, 6 months in the phase III clinical trials plus the open-label extension. The objective of this study was to assess the velocity of tophus resolution in subjects treated with pegloticase.MethodsData from two randomized controlled trials of pegloticase in chronic refractory gout were analyzed. Tophi were assessed by computer-assisted measurements of standardized digital photographs. Subjects were designated as responders and nonresponders based on maintenance of serum urate < 6 mg/dl at months 3 and 6 of treatment. The projected time of complete resolution of all tophi was determined by linear regression analysis.ResultsThe mean total tophus area at baseline was 585.8 mm2 for responders, 661.5 mm2 for nonresponders, and 674.4 mm2 for placebo-treated patients. Complete resolution at 6 months of at least one tophus was achieved by 69.6% of 23 responders, 27.9% of 43 nonresponders, and 14.3% of 21 patients who received placebo. Complete resolution of all photographed tophi was achieved by 34.8% of biochemical responders, 11.6% of nonresponders, and 0% of placebo-treated patients. The mean velocity of resolution of all tophi was 60.1 mm2/month in responders with a mean projected time of complete resolution of 9.9 months (4.6–32.6 months). There was a significant inverse correlation between serum urate AUC and tophus resolution velocity (r = − 0.40, P = 0.0002), although considerable heterogeneity in the velocity of resolution was noted. The only patient characteristic that correlated with the velocity of tophus resolution was the baseline tophus area.ConclusionsPegloticase treatment caused a rapid resolution of tophi in responders that correlated with the serum urate lowering associated with this therapy.
Highlights
Pegloticase is a recombinant mammalian uricase conjugated to polyethylene glycol approved in the United States for treatment of chronic refractory gout
The present analysis focuses on tophus reduction in patients who responded with persistent urate lowering to pegloticase and compares results from this group with those from patients who did not have a persistent response and those who received placebo
The mean time from onset of uratelowering therapy to the disappearance of the target tophus for all patients was 20.8 months. This is much longer than that reported in our analysis, and it is almost certainly related to the fact that the average on-treatment serum urate for the patients evaluated ranged from 3.97 to 5.37 mg/dl in different treatment arms of the trial reported by Perez-Ruiz vs an end-of-treatment value of 0.49 mg/dl for the biochemical responders in the present analysis
Summary
Pegloticase is a recombinant mammalian uricase conjugated to polyethylene glycol approved in the United States for treatment of chronic refractory gout. In patients receiving pegloticase who did not generate high-titer antidrug antibodies (responders), the serum urate remained low for the duration of therapy, 6 months in the phase III clinical trials plus the open-label extension. The tophus, a cardinal feature of gout, is a complex mass comprised of monosodium urate (MSU) crystals, a variety of immune and inflammatory cells, and a fibrous capsule [1, 2]. Tissue deposition of urate crystals initiates tophus formation with a local inflammatory and subsequent fibrotic tissue response. Tophaceous disease strongly predicts decreased hand function in patients with gout [14], because flexor or extensor tendon sheath deposition of urate can markedly reduce the ability to grasp and make a fist. The most recent guidelines for treatment of gout from the American College of Rheumatology recognize the impact of tophi on patients and recommend that “the target serum urate should be lowered sufficiently to durably improve signs and symptoms of gout, including palpable and visible tophi detected by physical examination, and that this may involve therapeutic serum urate-lowering to below 5 mg/dl” [16]
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